1QK9 , 3C2I
113-441: 4204 17257 ENSG00000169057 ENSMUSG00000031393 P51608 Q9Z2D6 NM_001369393 NM_001369394 NM_001386137 NM_001386138 NM_001386139 NM_001081979 NM_010788 NP_001356322 NP_001356323 NP_001075448 NP_034918 MECP2 ( methyl CpG binding protein 2 ) is a gene that encodes the protein MECP2. MECP2 appears to be essential for
226-475: A cytosine (C) when it occurs in a particular DNA sequence, " CpG ". This is a form of DNA methylation . Many genes have CpG islands , which frequently occur near the beginning of the gene. MECP2 does not bind to these islands in most cases, as they are not methylated. The expression of a few genes may be regulated through methylation of their CpG island, and MECP2 may play a role in a subset of these. Researchers have not yet determined which genes are targeted by
339-584: A promoter sequence. The promoter is recognized and bound by transcription factors that recruit and help RNA polymerase bind to the region to initiate transcription. The recognition typically occurs as a consensus sequence like the TATA box . A gene can have more than one promoter, resulting in messenger RNAs ( mRNA ) that differ in how far they extend in the 5' end. Highly transcribed genes have "strong" promoter sequences that form strong associations with transcription factors, thereby initiating transcription at
452-533: A " start codon ", and three " stop codons " indicate the beginning and end of the protein coding region . There are 64 possible codons (four possible nucleotides at each of three positions, hence 4 possible codons) and only 20 standard amino acids; hence the code is redundant and multiple codons can specify the same amino acid. The correspondence between codons and amino acids is nearly universal among all known living organisms. Chromatin Chromatin
565-457: A cell nucleus and the DNA is providing strength and direction to the mechanism of heredity. Moreover, between the nitrogenous bonds of the 2 DNA, homogenous bonds are forming. The basic repeat element of chromatin is the nucleosome, interconnected by sections of linker DNA , a far shorter arrangement than pure DNA in solution. In addition to core histones, a linker histone H1 exists that contacts
678-508: A code structure with four chemical bases such as “Adenine (A), Guanine (G), Cytosine (C), and Thymine (T)” . The order and sequences of these chemical structures of DNA are reflected as information available for the creation and control of human organisms. “A with T and C with G” pairing up to build the DNA base pair. Sugar and phosphate molecules are also paired with these bases, making DNA nucleotides arrange 2 long spiral strands unitedly called “double helix” . In eukaryotes, DNA consists of
791-608: A compaction state close to its pre-damage level after about 20 min. It has been a puzzle how decondensed interphase chromosomes remain essentially unknotted. The natural expectation is that in the presence of type II DNA topoisomerases that permit passages of double-stranded DNA regions through each other, all chromosomes should reach the state of topological equilibrium. The topological equilibrium in highly crowded interphase chromosomes forming chromosome territories would result in formation of highly knotted chromatin fibres. However, Chromosome Conformation Capture (3C) methods revealed that
904-445: A continuous messenger RNA , referred to as a polycistronic mRNA . The term cistron in this context is equivalent to gene. The transcription of an operon's mRNA is often controlled by a repressor that can occur in an active or inactive state depending on the presence of specific metabolites. When active, the repressor binds to a DNA sequence at the beginning of the operon, called the operator region , and represses transcription of
1017-539: A disorder, but after about six months to a year and half, speech and motor function capabilities start to decrease. This is followed by seizures , growth retardation and cognitive and motor impairment. The MECP2 locus is X-linked and the disease-causing alleles are dominant . Due to its prevalence in females, it has been linked to male lethality, or to a predominant transmission with the paternal X chromosome; nevertheless, in rare cases some males can also be affected by Rett Syndrome. Males with gene duplications of MECP-2 at
1130-449: A double-helix run in opposite directions. Nucleic acid synthesis, including DNA replication and transcription occurs in the 5'→3' direction, because new nucleotides are added via a dehydration reaction that uses the exposed 3' hydroxyl as a nucleophile . The expression of genes encoded in DNA begins by transcribing the gene into RNA , a second type of nucleic acid that is very similar to DNA, but whose monomers contain
1243-408: A dynamic, liquid-like domain. Decreased chromatin compaction comes with increased chromatin mobility and easier transcriptional access to DNA. The phenomenon, as opposed to simple probabilistic models of transcription, can account for the high variability in gene expression occurring between cells in isogenic populations. During metazoan spermiogenesis , the spermatid 's chromatin is remodeled into
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#17328847219511356-488: A few genes and are transferable between individuals. For example, the genes for antibiotic resistance are usually encoded on bacterial plasmids and can be passed between individual cells, even those of different species, via horizontal gene transfer . Whereas the chromosomes of prokaryotes are relatively gene-dense, those of eukaryotes often contain regions of DNA that serve no obvious function. Simple single-celled eukaryotes have relatively small amounts of such DNA, whereas
1469-434: A gene - surprisingly, there is no definition that is entirely satisfactory. A gene is a DNA sequence that codes for a diffusible product. This product may be protein (as is the case in the majority of genes) or may be RNA (as is the case of genes that code for tRNA and rRNA). The crucial feature is that the product diffuses away from its site of synthesis to act elsewhere. The important parts of such definitions are: (1) that
1582-443: A gene can be found in the articles Genetics and Gene-centered view of evolution . The molecular gene definition is more commonly used across biochemistry, molecular biology, and most of genetics — the gene that is described in terms of DNA sequence. There are many different definitions of this gene — some of which are misleading or incorrect. Very early work in the field that became molecular genetics suggested
1695-565: A gene corresponds to a transcription unit; (2) that genes produce both mRNA and noncoding RNAs; and (3) regulatory sequences control gene expression but are not part of the gene itself. However, there's one other important part of the definition and it is emphasized in Kostas Kampourakis' book Making Sense of Genes . Therefore in this book I will consider genes as DNA sequences encoding information for functional products, be it proteins or RNA molecules. With 'encoding information', I mean that
1808-410: A gene may be split across chromosomes but those transcripts are concatenated back together into a functional sequence by trans-splicing . It is also possible for overlapping genes to share some of their DNA sequence, either on opposite strands or the same strand (in a different reading frame, or even the same reading frame). In all organisms, two steps are required to read the information encoded in
1921-404: A gene's DNA and produce the protein it specifies. First, the gene's DNA is transcribed to messenger RNA ( mRNA ). Second, that mRNA is translated to protein. RNA-coding genes must still go through the first step, but are not translated into protein. The process of producing a biologically functional molecule of either RNA or protein is called gene expression , and the resulting molecule
2034-411: A gene), DNA is first copied into RNA . RNA can be directly functional or be the intermediate template for the synthesis of a protein. The transmission of genes to an organism's offspring , is the basis of the inheritance of phenotypic traits from one generation to the next. These genes make up different DNA sequences, together called a genotype , that is specific to every given individual, within
2147-565: A gene: that of bacteriophage MS2 coat protein. The subsequent development of chain-termination DNA sequencing in 1977 by Frederick Sanger improved the efficiency of sequencing and turned it into a routine laboratory tool. An automated version of the Sanger method was used in early phases of the Human Genome Project . The theories developed in the early 20th century to integrate Mendelian genetics with Darwinian evolution are called
2260-439: A gene; however, members of a population may have different alleles at the locus, each with a slightly different gene sequence. The majority of eukaryotic genes are stored on a set of large, linear chromosomes. The chromosomes are packed within the nucleus in complex with storage proteins called histones to form a unit called a nucleosome . DNA packaged and condensed in this way is called chromatin . The manner in which DNA
2373-448: A high rate. Others genes have "weak" promoters that form weak associations with transcription factors and initiate transcription less frequently. Eukaryotic promoter regions are much more complex and difficult to identify than prokaryotic promoters. Additionally, genes can have regulatory regions many kilobases upstream or downstream of the gene that alter expression. These act by binding to transcription factors which then cause
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#17328847219512486-458: A homeostatic mechanism that could regulate MECP2 levels in the brain. MeCP2 in the developing rat brain regulates important social development in a sexually dimorphic manner. MeCP2 levels are different between males and females in the developing rat brain 24 hours after birth within the amygdala and hypothalamus , but this difference is no longer observed 10 days after birth. Specifically, males express less MeCP2 than females, and this aligns with
2599-420: A lack of gene product. This defect probably disrupts the normal functioning of nerve cells, leading to the signs and symptoms of Rett syndrome. Rett syndrome is mainly found in girls with a prevalence of around 1 in every 10,000; male fetuses with normal karyotypes afflicted with this condition rarely survive to term and if so, usually die shortly after birth. Patients are born with very hard to find signs of
2712-548: A more spaced-packaged, widened, almost crystal-like structure. This process is associated with the cessation of transcription and involves nuclear protein exchange. The histones are mostly displaced, and replaced by protamines (small, arginine -rich proteins). It is proposed that in yeast, regions devoid of histones become very fragile after transcription; HMO1, an HMG-box protein, helps in stabilizing nucleosomes-free chromatin. A variety of internal and external agents can cause DNA damage in cells. Many factors influence how
2825-572: A new expanded definition that includes noncoding genes. However, some modern writers still do not acknowledge noncoding genes although this so-called "new" definition has been recognised for more than half a century. Although some definitions can be more broadly applicable than others, the fundamental complexity of biology means that no definition of a gene can capture all aspects perfectly. Not all genomes are DNA (e.g. RNA viruses ), bacterial operons are multiple protein-coding regions transcribed into single large mRNAs, alternative splicing enables
2938-400: A process known as RNA splicing . Finally, the ends of gene transcripts are defined by cleavage and polyadenylation (CPA) sites , where newly produced pre-mRNA gets cleaved and a string of ~200 adenosine monophosphates is added at the 3' end. The poly(A) tail protects mature mRNA from degradation and has other functions, affecting translation, localization, and transport of the transcript from
3051-419: A protein-coding gene consists of many elements of which the actual protein coding sequence is often only a small part. These include introns and untranslated regions of the mature mRNA. Noncoding genes can also contain introns that are removed during processing to produce the mature functional RNA. All genes are associated with regulatory sequences that are required for their expression. First, genes require
3164-460: A second, with half maximum accumulation within 1.6 seconds after the damage occurs. Next the chromatin remodeler Alc1 quickly attaches to the product of PARP1, and completes arrival at the DNA damage within 10 seconds of the damage. About half of the maximum chromatin relaxation, presumably due to action of Alc1, occurs by 10 seconds. This then allows recruitment of the DNA repair enzyme MRE11 , to initiate DNA repair, within 13 seconds. γH2AX,
3277-412: A single genomic region to encode multiple district products and trans-splicing concatenates mRNAs from shorter coding sequence across the genome. Since molecular definitions exclude elements such as introns, promotors, and other regulatory regions , these are instead thought of as "associated" with the gene and affect its function. An even broader operational definition is sometimes used to encompass
3390-472: A strict definition of the word "gene" with which nearly every expert can agree. First, in order for a nucleotide sequence to be considered a true gene, an open reading frame (ORF) must be present. The ORF can be thought of as the "gene itself"; it begins with a starting mark common for every gene and ends with one of three possible finish line signals. One of the key enzymes in this process, the RNA polymerase, zips along
3503-403: A tendency to form loops. These loops allow interactions between different regions of DNA by bringing them closer to each other, which increases the efficiency of gene interactions. This process is dynamic, with loops forming and disappearing. The loops are regulated by two main elements: There are many other elements involved. For example, Jpx regulates the binding sites of CTCF molecules along
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3616-409: A true gene, by this definition, one has to prove that the transcript has a biological function. Early speculations on the size of a typical gene were based on high-resolution genetic mapping and on the size of proteins and RNA molecules. A length of 1500 base pairs seemed reasonable at the time (1965). This was based on the idea that the gene was the DNA that was directly responsible for production of
3729-468: A way that knots would be efficiently unknotted instead of making the knots even more complex. It has been shown that the process of chromatin-loop extrusion is ideally suited to actively unknot chromatin fibres in interphase chromosomes. The term, introduced by Walther Flemming , has multiple meanings: The first definition allows for "chromatins" to be defined in other domains of life like bacteria and archaea, using any DNA-binding proteins that condenses
3842-415: A wedge and attaches to the methylated CpG sites on the DNA strands. The TRD region then reacts with SIN3A to recruit histone deacetylases (HDAC). There are also unusual, repetitive sequences found at the carboxyl terminus. This region is closely related to the fork head family, at the amino acid level. The role of MECP2 in disease is primarily associated with either a loss of function (under expression) of
3955-440: Is a complex of DNA and protein found in eukaryotic cells. The primary function is to package long DNA molecules into more compact, denser structures. This prevents the strands from becoming tangled and also plays important roles in reinforcing the DNA during cell division , preventing DNA damage , and regulating gene expression and DNA replication . During mitosis and meiosis , chromatin facilitates proper segregation of
4068-460: Is a left-handed helix with a zig-zag phosphate backbone. Z-DNA is thought to play a specific role in chromatin structure and transcription because of the properties of the junction between B- and Z-DNA. At the junction of B- and Z-DNA, one pair of bases is flipped out from normal bonding. These play a dual role of a site of recognition by many proteins and as a sink for torsional stress from RNA polymerase or nucleosome binding.DNA bases are stored as
4181-503: Is about two million base pairs at the site of a DNA double-strand break. γH2AX does not, itself, cause chromatin decondensation, but within 30 seconds of irradiation, RNF8 protein can be detected in association with γH2AX. RNF8 mediates extensive chromatin decondensation, through its subsequent interaction with CHD4 , a component of the nucleosome remodeling and deacetylase complex NuRD . After undergoing relaxation subsequent to DNA damage, followed by DNA repair, chromatin recovers to
4294-456: Is called a gene product . The nucleotide sequence of a gene's DNA specifies the amino acid sequence of a protein through the genetic code . Sets of three nucleotides, known as codons , each correspond to a specific amino acid. The principle that three sequential bases of DNA code for each amino acid was demonstrated in 1961 using frameshift mutations in the rIIB gene of bacteriophage T4 (see Crick, Brenner et al. experiment ). Additionally,
4407-409: Is called a genophore and is localized within the nucleoid region). The overall structure of the chromatin network further depends on the stage of the cell cycle . During interphase , the chromatin is structurally loose to allow access to RNA and DNA polymerases that transcribe and replicate the DNA. The local structure of chromatin during interphase depends on the specific genes present in
4520-489: Is due primarily to the varying physical properties of different DNA sequences: For instance, adenine (A), and thymine (T) is more favorably compressed into the inner minor grooves. This means nucleosomes can bind preferentially at one position approximately every 10 base pairs (the helical repeat of DNA)- where the DNA is rotated to maximise the number of A and T bases that will lie in the inner minor groove. (See nucleic acid structure .) With addition of H1, during mitosis
4633-402: Is found in high concentrations in neurons and is associated with maturation of the central nervous system (CNS) and in forming synaptic contacts . The MeCP2 protein binds to forms of DNA that have been methylated . The MeCP2 protein then interacts with other proteins to form a complex that turns off the gene. MeCP2 prefers to bind to sites on the genome with a chemical alteration made to
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4746-578: Is gone by adulthood. MeCP2 monitors the response to early life stress. Early life stress is correlated with hyper-phosphorylation of the MeCP2 protein in paraventricular nucleus of the hypothalamus. This thus causes a reduced occupancy of MeCP2 at the AVP gene's promoter region, and therefore elevated levels of AVP. Vasopressin is a primary hormone involved in the Hypothalmic-Pituitary-Adrenal Axis,
4859-458: Is known to regulate many social behaviors including pair bonding and social recognition. While male rats typically have higher levels of vasopressin in the amygdala, MeCP2 reduction during the first 3 days of life causes a lasting reduction of vasopressin to female typical levels in this brain region that lasted through adulthood. Male rats with reduced MeCP2 levels also show a significant reduction of AR at two weeks following infusion, but this effect
4972-468: Is limited understanding of chromatin structure and it is active area of research in molecular biology . Chromatin undergoes various structural changes during a cell cycle . Histone proteins are the basic packers and arrangers of chromatin and can be modified by various post-translational modifications to alter chromatin packing ( histone modification ). Most modifications occur on histone tails. The positively charged histone cores only partially counteract
5085-433: Is located on the long (q) arm of the X chromosome in band 28 ("Xq28"), from base pair 152,808,110 to base pair 152,878,611. MECP2 is an important reader of DNA methylation. Its methyl-CpG-binding (MBD) domain recognizes and binds 5-mC regions. MECP2 is X-linked and subject to X inactivation . MECP2 gene mutations are the cause of most cases of Rett syndrome , a progressive neurologic developmental disorder and one of
5198-400: Is nearly the same for all known organisms. The total complement of genes in an organism or cell is known as its genome , which may be stored on one or more chromosomes . A chromosome consists of a single, very long DNA helix on which thousands of genes are encoded. The region of the chromosome at which a particular gene is located is called its locus . Each locus contains one allele of
5311-401: Is processed into a protein ( RNA splicing ). Mutations in the gene alter the structure of the MeCP2 protein or lead to reduced amounts of the protein. As a result, the protein is unable to bind to DNA or turn other genes on or off. Genes that are normally repressed by MeCP2 remain active when their products are not needed. Other genes that are normally activated by MeCP2 remain inactive leading to
5424-546: Is relatively resistant to bending and rotation. This makes the length of linker DNA critical to the stability of the fibre, requiring nucleosomes to be separated by lengths that permit rotation and folding into the required orientation without excessive stress to the DNA. In this view, different lengths of the linker DNA should produce different folding topologies of the chromatin fiber. Recent theoretical work, based on electron-microscopy images of reconstituted fibers supports this view. The beads-on-a-string chromatin structure has
5537-403: Is still part of the definition of a gene in most textbooks. For example, The primary function of the genome is to produce RNA molecules. Selected portions of the DNA nucleotide sequence are copied into a corresponding RNA nucleotide sequence, which either encodes a protein (if it is an mRNA) or forms a 'structural' RNA, such as a transfer RNA (tRNA) or ribosomal RNA (rRNA) molecule. Each region of
5650-399: Is stored on the histones, as well as chemical modifications of the histone itself, regulate whether a particular region of DNA is accessible for gene expression . In addition to genes, eukaryotic chromosomes contain sequences involved in ensuring that the DNA is copied without degradation of end regions and sorted into daughter cells during cell division: replication origins , telomeres , and
5763-558: The MECP2 gene as in Rett syndrome or in a gain of function (over expression) as in MECP2 duplication syndrome . Many mutations have been associated with loss of expression of the MECP2 gene and have been identified in Rett syndrome patients. These mutations include changes in single DNA base pairs ( SNP ), insertions or deletions of DNA in the MECP2 gene, and changes that affect how the gene information
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#17328847219515876-607: The MECP2 gene. Lastly, MECP2 mutations or changes in the gene's activity have been reported in some cases of autism (a developmental disorder that affects communication and social interaction). More recent studies reported genetic polymorphisms in the MeCP2 gene in patients with systemic lupus erythematosus (SLE). SLE is a systemic autoimmune disease that can affect multiple organs. MeCP2 polymorphisms have been reported so far in European-derived and Asian lupus patients. The genetic loss of MECP2 has been identified as changing
5989-511: The aging process. The centromere is required for binding spindle fibres to separate sister chromatids into daughter cells during cell division . Prokaryotes ( bacteria and archaea ) typically store their genomes on a single, large, circular chromosome . Similarly, some eukaryotic organelles contain a remnant circular chromosome with a small number of genes. Prokaryotes sometimes supplement their chromosome with additional small circles of DNA called plasmids , which usually encode only
6102-401: The beads-on-a-string structure can coil into a 30 nm-diameter helical structure known as the 30 nm fibre or filament. The precise structure of the chromatin fiber in the cell is not known in detail. This level of chromatin structure is thought to be the form of heterochromatin , which contains mostly transcriptionally silent genes. Electron microscopy studies have demonstrated that
6215-401: The central dogma of molecular biology , which states that proteins are translated from RNA , which is transcribed from DNA . This dogma has since been shown to have exceptions, such as reverse transcription in retroviruses . The modern study of genetics at the level of DNA is known as molecular genetics . In 1972, Walter Fiers and his team were the first to determine the sequence of
6328-419: The centromere . Replication origins are the sequence regions where DNA replication is initiated to make two copies of the chromosome. Telomeres are long stretches of repetitive sequences that cap the ends of the linear chromosomes and prevent degradation of coding and regulatory regions during DNA replication . The length of the telomeres decreases each time the genome is replicated and has been implicated in
6441-421: The chromatin structure, form a complex with histone deacetylases (HDAC), or block transcription factors directly. More recent studies have demonstrated that MeCP2 may also function as a transcriptional activator, through recruiting the transcription factor CREB1 . This was an unexpected finding which suggests that MeCP2 is a key transcriptional regulator with potentially dual roles in gene expression. In fact,
6554-881: The chromosomes in anaphase ; the characteristic shapes of chromosomes visible during this stage are the result of DNA being coiled into highly condensed chromatin. The primary protein components of chromatin are histones . An octamer of two sets of four histone cores ( Histone H2A , Histone H2B , Histone H3 , and Histone H4 ) bind to DNA and function as "anchors" around which the strands are wound. In general, there are three levels of chromatin organization: Many organisms, however, do not follow this organization scheme. For example, spermatozoa and avian red blood cells have more tightly packed chromatin than most eukaryotic cells, and trypanosomatid protozoa do not condense their chromatin into visible chromosomes at all. Prokaryotic cells have entirely different structures for organizing their DNA (the prokaryotic chromosome equivalent
6667-444: The gene pool of the population of a given species . The genotype, along with environmental and developmental factors, ultimately determines the phenotype of the individual. Most biological traits occur under the combined influence of polygenes (a set of different genes) and gene–environment interactions . Some genetic traits are instantly visible, such as eye color or the number of limbs, others are not, such as blood type ,
6780-549: The modern synthesis , a term introduced by Julian Huxley . This view of evolution was emphasized by George C. Williams ' gene-centric view of evolution . He proposed that the Mendelian gene is a unit of natural selection with the definition: "that which segregates and recombines with appreciable frequency." Related ideas emphasizing the centrality of Mendelian genes and the importance of natural selection in evolution were popularized by Richard Dawkins . The development of
6893-475: The neutral theory of evolution in the late 1960s led to the recognition that random genetic drift is a major player in evolution and that neutral theory should be the null hypothesis of molecular evolution. This led to the construction of phylogenetic trees and the development of the molecular clock , which is the basis of all dating techniques using DNA sequences. These techniques are not confined to molecular gene sequences but can be used on all DNA segments in
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#17328847219517006-750: The operon ; when the repressor is inactive transcription of the operon can occur (see e.g. Lac operon ). The products of operon genes typically have related functions and are involved in the same regulatory network . Though many genes have simple structures, as with much of biology, others can be quite complex or represent unusual edge-cases. Eukaryotic genes often have introns that are much larger than their exons, and those introns can even have other genes nested inside them . Associated enhancers may be many kilobase away, or even on entirely different chromosomes operating via physical contact between two chromosomes. A single gene can encode multiple different functional products by alternative splicing , and conversely
7119-417: The 30 nm fiber is highly dynamic such that it unfolds into a 10 nm fiber beads-on-a-string structure when transversed by an RNA polymerase engaged in transcription. The existing models commonly accept that the nucleosomes lie perpendicular to the axis of the fibre, with linker histones arranged internally. A stable 30 nm fibre relies on the regular positioning of nucleosomes along DNA. Linker DNA
7232-468: The DNA fiber. The spatial arrangement of the chromatin within the nucleus is not random - specific regions of the chromatin can be found in certain territories. Territories are, for example, the lamina-associated domains (LADs), and the topologically associating domains (TADs), which are bound together by protein complexes. Currently, polymer models such as the Strings & Binders Switch (SBS) model and
7345-404: The DNA helix that produces a functional RNA molecule constitutes a gene. We define a gene as a DNA sequence that is transcribed. This definition includes genes that do not encode proteins (not all transcripts are messenger RNA). The definition normally excludes regions of the genome that control transcription but are not themselves transcribed. We will encounter some exceptions to our definition of
7458-450: The DNA sequence is used as a template for the production of an RNA molecule or a protein that performs some function. The emphasis on function is essential because there are stretches of DNA that produce non-functional transcripts and they do not qualify as genes. These include obvious examples such as transcribed pseudogenes as well as less obvious examples such as junk RNA produced as noise due to transcription errors. In order to qualify as
7571-766: The DNA to loop so that the regulatory sequence (and bound transcription factor) become close to the RNA polymerase binding site. For example, enhancers increase transcription by binding an activator protein which then helps to recruit the RNA polymerase to the promoter; conversely silencers bind repressor proteins and make the DNA less available for RNA polymerase. The mature messenger RNA produced from protein-coding genes contains untranslated regions at both ends which contain binding sites for ribosomes , RNA-binding proteins , miRNA , as well as terminator , and start and stop codons . In addition, most eukaryotic open reading frames contain untranslated introns , which are removed and exons , which are connected together in
7684-519: The DNA. Regions of DNA containing genes which are actively transcribed ("turned on") are less tightly compacted and closely associated with RNA polymerases in a structure known as euchromatin , while regions containing inactive genes ("turned off") are generally more condensed and associated with structural proteins in heterochromatin . Epigenetic modification of the structural proteins in chromatin via methylation and acetylation also alters local chromatin structure and therefore gene expression. There
7797-455: The Dynamic Loop (DL) model are used to describe the folding of chromatin within the nucleus. The arrangement of chromatin within the nucleus may also play a role in nuclear stress and restoring nuclear membrane deformation by mechanical stress. When chromatin is condensed, the nucleus becomes more rigid. When chromatin is decondensed, the nucleus becomes more elastic with less force exerted on
7910-514: The MeCP2 protein, but such genes are probably important for the normal function of the central nervous system. However, the first large-scale mapping of MECP2 binding sites in neurons found that only 6% of the binding sites are in CpG islands, and that 63% of MECP2-bound promoters are actively expressed and only 6% are highly methylated, indicating that MECP2's main function is something other than silencing methylated promoters. Once bound, MeCP2 will condense
8023-751: The Xq28 locus are also at risk for recurrent infections & meningitis in infancy. Mutations in the MECP2 gene have also been identified in people with several other disorders affecting the central nervous system. For example, MECP2 mutations are associated with some cases of moderate to severe X-linked mental retardation. Mutations in the gene have also been found in males with severe brain dysfunction ( neonatal encephalopathy ) who live only into early childhood. In addition, several people with features of both Rett syndrome and Angelman syndrome (a condition characterized by mental retardation, problems with movement, and inappropriate laughter and excitability) have mutations in
8136-433: The adenines of one strand are paired with the thymines of the other strand, and so on. Due to the chemical composition of the pentose residues of the bases, DNA strands have directionality. One end of a DNA polymer contains an exposed hydroxyl group on the deoxyribose ; this is known as the 3' end of the molecule. The other end contains an exposed phosphate group; this is the 5' end . The two strands of
8249-521: The alleles. There are many different ways to use the term "gene" based on different aspects of their inheritance, selection, biological function, or molecular structure but most of these definitions fall into two categories, the Mendelian gene or the molecular gene. The Mendelian gene is the classical gene of genetics and it refers to any heritable trait. This is the gene described in The Selfish Gene . More thorough discussions of this version of
8362-482: The association and dissociation of transcription factor complexes with chromatin. Specifically, RNA polymerase and transcriptional proteins have been shown to congregate into droplets via phase separation, and recent studies have suggested that 10 nm chromatin demonstrates liquid-like behavior increasing the targetability of genomic DNA. The interactions between linker histones and disordered tail regions act as an electrostatic glue organizing large-scale chromatin into
8475-442: The cells accumulated more damaged DNA and were more prone to cell death than control cells. It was concluded that reduced MECP2 expression causes reduced capacity to repair DNA and this likely contributes to neurological decline. MECP2 is part of a family of methyl-CpG-binding domain proteins (MBD), but possesses its own unique differences which help set it apart from the group. It has two functional domains: The MBD domain forms
8588-402: The complexity of these diverse phenomena, where a gene is defined as a union of genomic sequences encoding a coherent set of potentially overlapping functional products. This definition categorizes genes by their functional products (proteins or RNA) rather than their specific DNA loci, with regulatory elements classified as gene-associated regions. The existence of discrete inheritable units
8701-399: The concept that one gene makes one protein (originally 'one gene - one enzyme'). However, genes that produce repressor RNAs were proposed in the 1950s and by the 1960s, textbooks were using molecular gene definitions that included those that specified functional RNA molecules such as ribosomal RNA and tRNA (noncoding genes) as well as protein-coding genes. This idea of two kinds of genes
8814-406: The condition of chromatin, and the constantly changing chromatin environment has a large effect on it. Accessing and repairing the damaged cell of DNA, the genome condenses into chromatin and repairing it through modifying the histone residues. Through altering the chromatin structure, histones residues are adding chemical groups namely phosphate, acetyl and one or more methyl groups and these control
8927-596: The connectivity in the brain that regulates processing of and reaction to stress. Decreased functioning of the MeCP2 protein thus upregulates the neuronal stress response. Gene In biology , the word gene has two meanings. The Mendelian gene is a basic unit of heredity . The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA . There are two types of molecular genes: protein-coding genes and non-coding genes. During gene expression (the synthesis of RNA or protein from
9040-410: The critical cellular process of DNA repair, the chromatin must be remodeled. In eukaryotes, ATP-dependent chromatin remodeling complexes and histone-modifying enzymes are two predominant factors employed to accomplish this remodeling process. Chromatin relaxation occurs rapidly at the site of DNA damage. This process is initiated by PARP1 protein that starts to appear at DNA damage in less than
9153-441: The decay of contacts with the genomic distance in interphase chromosomes is practically the same as in the crumpled globule state that is formed when long polymers condense without formation of any knots. To remove knots from highly crowded chromatin, one would need an active process that should not only provide the energy to move the system from the state of topological equilibrium but also guide topoisomerase-mediated passages in such
9266-524: The distinction between a heterozygote and homozygote , and the phenomenon of discontinuous inheritance. Prior to Mendel's work, the dominant theory of heredity was one of blending inheritance , which suggested that each parent contributed fluids to the fertilization process and that the traits of the parents blended and mixed to produce the offspring. Charles Darwin developed a theory of inheritance he termed pangenesis , from Greek pan ("all, whole") and genesis ("birth") / genos ("origin"). Darwin used
9379-552: The dynamics of the chromatin which shows that acetylation of H4 at K16 is vital for proper intra- and inter- functionality of chromatin structure. Polycomb-group proteins play a role in regulating genes through modulation of chromatin structure. For additional information, see Chromatin variant , Histone modifications in chromatin regulation and RNA polymerase control by chromatin structure . In nature, DNA can form three structures, A- , B- , and Z-DNA . A- and B-DNA are very similar, forming right-handed helices, whereas Z-DNA
9492-410: The early 1950s the prevailing view was that the genes in a chromosome acted like discrete entities arranged like beads on a string. The experiments of Benzer using mutants defective in the rII region of bacteriophage T4 (1955–1959) showed that individual genes have a simple linear structure and are likely to be equivalent to a linear section of DNA. Collectively, this body of research established
9605-402: The end of the histones is positively charged. The acetylation of these tails would make the chromatin ends neutral, allowing for DNA access. When the chromatin decondenses, the DNA is open to entry of molecular machinery. Fluctuations between open and closed chromatin may contribute to the discontinuity of transcription, or transcriptional bursting . Other factors are probably involved, such as
9718-493: The exit/entry of the DNA strand on the nucleosome. The nucleosome core particle, together with histone H1, is known as a chromatosome . Nucleosomes, with about 20 to 60 base pairs of linker DNA, can form, under non-physiological conditions, an approximately 11 nm beads on a string fibre. The nucleosomes bind DNA non-specifically, as required by their function in general DNA packaging. There are, however, large DNA sequence preferences that govern nucleosome positioning. This
9831-503: The expressions of gene building by proteins to acquire DNA. Moreover, resynthesis of the delighted zone, DNA will be repaired by processing and restructuring the damaged bases. In order to maintain genomic integrity, “homologous recombination and classical non-homologous end joining process” has been followed by DNA to be repaired. The packaging of eukaryotic DNA into chromatin presents a barrier to all DNA-based processes that require recruitment of enzymes to their sites of action. To allow
9944-514: The fact that both protein-coding genes and noncoding genes have been known for more than 50 years, there are still a number of textbooks, websites, and scientific publications that define a gene as a DNA sequence that specifies a protein. In other words, the definition is restricted to protein-coding genes. Here is an example from a recent article in American Scientist. ... to truly assess the potential significance of de novo genes, we relied on
10057-413: The functional product. The discovery of introns in the 1970s meant that many eukaryotic genes were much larger than the size of the functional product would imply. Typical mammalian protein-coding genes, for example, are about 62,000 base pairs in length (transcribed region) and since there are about 20,000 of them they occupy about 35–40% of the mammalian genome (including the human genome). In spite of
10170-421: The genome. The vast majority of organisms encode their genes in long strands of DNA (deoxyribonucleic acid). DNA consists of a chain made from four types of nucleotide subunits, each composed of: a five-carbon sugar ( 2-deoxyribose ), a phosphate group, and one of the four bases adenine , cytosine , guanine , and thymine . Two chains of DNA twist around each other to form a DNA double helix with
10283-421: The genomes of complex multicellular organisms , including humans, contain an absolute majority of DNA without an identified function. This DNA has often been referred to as " junk DNA ". However, more recent analyses suggest that, although protein-coding DNA makes up barely 2% of the human genome , about 80% of the bases in the genome may be expressed, so the term "junk DNA" may be a misnomer. The structure of
10396-467: The inner nuclear membrane. This observation sheds light on other possible cellular functions of chromatin organization outside of genomic regulation. Chromatin and its interaction with enzymes has been researched, and a conclusion being made is that it is relevant and an important factor in gene expression. Vincent G. Allfrey, a professor at Rockefeller University, stated that RNA synthesis is related to histone acetylation. The lysine amino acid attached to
10509-646: The level of chromatin compaction will alter. The consequences in terms of chromatin accessibility and compaction depend both on the modified amino acid and the type of modification. For example, histone acetylation results in loosening and increased accessibility of chromatin for replication and transcription. Lysine trimethylation can either lead to increased transcriptional activity ( trimethylation of histone H3 lysine 4 ) or transcriptional repression and chromatin compaction ( trimethylation of histone H3, lysine 9 or lysine 27 ). Several studies suggested that different modifications could occur simultaneously. For example, it
10622-449: The locus ceruleus is a critical site at which loss of MECP2 results in CNS dysfunction." Click on genes, proteins and metabolites below to visit related articles. MECP2 has been shown to interact with SKI protein and Nuclear receptor co-repressor 1 . In neuronal cells the MECP2 mRNA is thought to interact with miR-132 , which silences the expression of the protein. This forms part of
10735-743: The majority of genes that are regulated by MeCP2 appear to be activated rather than repressed. However, it remains controversial whether MeCP2 regulates these genes directly or whether these changes are secondary in nature. Further studies have shown MeCP2 may be able to bind directly to un-methylated DNA in some instances. MeCP2 has been implicated in regulation of imprinted genes and loci that include UBE3A and DLX5 . Reduced expression of MECP2 in Mecp2+/- neural stem cells causes an increase in senescence , impairment of proliferative capacity and accumulation of unrepaired DNA damage . After treatment of Mecp2+/- cells with any of three different DNA damaging agents,
10848-403: The most common causes of cognitive disability in females. At least 53 disease-causing mutations in this gene have been discovered. MECP2 protein is found in all cells in the body, including the brain , acting as a transcriptional repressor and activator, depending on the context. However, the idea that MECP2 functions as an activator is relatively new and remains controversial. In the brain, it
10961-407: The negative charge of the DNA phosphate backbone resulting in a negative net charge of the overall structure. An imbalance of charge within the polymer causes electrostatic repulsion between neighboring chromatin regions that promote interactions with positively charged proteins, molecules, and cations. As these modifications occur, the electrostatic environment surrounding the chromatin will flux and
11074-407: The normal function of nerve cells . The protein seems to be particularly important for mature nerve cells, where it is present in high levels. The MECP2 protein is likely to be involved in turning off ("repressing" or " silencing ") several other genes. This prevents the genes from making proteins when they are not needed. Recent work has shown that MECP2 can also activate other genes. The MECP2 gene
11187-413: The nucleus. Splicing, followed by CPA, generate the final mature mRNA , which encodes the protein or RNA product. Many noncoding genes in eukaryotes have different transcription termination mechanisms and they do not have poly(A) tails. Many prokaryotic genes are organized into operons , with multiple protein-coding sequences that are transcribed as a unit. The genes in an operon are transcribed as
11300-431: The phosphate–sugar backbone spiralling around the outside, and the bases pointing inward with adenine base pairing to thymine and guanine to cytosine. The specificity of base pairing occurs because adenine and thymine align to form two hydrogen bonds , whereas cytosine and guanine form three hydrogen bonds. The two strands in a double helix must, therefore, be complementary , with their sequence of bases matching such that
11413-532: The phosphorylated form of H2AX is also involved in the early steps leading to chromatin decondensation after DNA damage occurrence. The histone variant H2AX constitutes about 10% of the H2A histones in human chromatin. γH2AX (H2AX phosphorylated on serine 139) can be detected as soon as 20 seconds after irradiation of cells (with DNA double-strand break formation), and half maximum accumulation of γH2AX occurs in one minute. The extent of chromatin with phosphorylated γH2AX
11526-416: The properties of cells in the locus ceruleus , the exclusive source of noradrenergic innervation to the cerebral cortex and hippocampus . Researchers have concluded that "Because these neurons are a pivotal source of norepinephrine throughout the brainstem and forebrain and are involved in the regulation of diverse functions disrupted in Rett syndrome, such as respiration and cognition, we hypothesize that
11639-528: The repair route is selected, including the cell cycle phase and chromatin segment where the break occurred. In terms of initiating 5’ end DNA repair, the p53 binding protein 1 ( 53BP1 ) and BRCA1 are important protein components that influence double-strand break repair pathway selection. The 53BP1 complex attaches to chromatin near DNA breaks and activates downstream factors such as Rap1-Interacting Factor 1 ( RIF1 ) and shieldin, which protects DNA ends against nucleolytic destruction. DNA damage process occurs within
11752-431: The risk for specific diseases, or the thousands of basic biochemical processes that constitute life . A gene can acquire mutations in its sequence , leading to different variants, known as alleles , in the population . These alleles encode slightly different versions of a gene, which may cause different phenotypical traits. Genes evolve due to natural selection or survival of the fittest and genetic drift of
11865-531: The steroid-sensitive time period of the neonatal rat brain. Reductions in MeCP2 with Small interfering RNA (siRNA) during the first few days of life reduce male levels of juvenile social play behavior to female typical levels, but do not affect female juvenile play behavior. MeCP2 is important in organizing hormone-related behaviors and sex differences in the developing rat amygdala. MeCP2 appears to regulate arginine vasopressin (AVP) and androgen receptor (AR) production in male rats but not in females. Vasopressin
11978-467: The strand of DNA like a train on a monorail, transcribing it into its messenger RNA form. This point brings us to our second important criterion: A true gene is one that is both transcribed and translated. That is, a true gene is first used as a template to make transient messenger RNA, which is then translated into a protein. This restricted definition is so common that it has spawned many recent articles that criticize this "standard definition" and call for
12091-461: The sugar ribose rather than deoxyribose . RNA also contains the base uracil in place of thymine . RNA molecules are less stable than DNA and are typically single-stranded. Genes that encode proteins are composed of a series of three- nucleotide sequences called codons , which serve as the "words" in the genetic "language". The genetic code specifies the correspondence during protein translation between codons and amino acids . The genetic code
12204-805: The term gemmule to describe hypothetical particles that would mix during reproduction. Mendel's work went largely unnoticed after its first publication in 1866, but was rediscovered in the late 19th century by Hugo de Vries , Carl Correns , and Erich von Tschermak , who (claimed to have) reached similar conclusions in their own research. Specifically, in 1889, Hugo de Vries published his book Intracellular Pangenesis , in which he postulated that different characters have individual hereditary carriers and that inheritance of specific traits in organisms comes in particles. De Vries called these units "pangenes" ( Pangens in German), after Darwin's 1868 pangenesis theory. Twenty years later, in 1909, Wilhelm Johannsen introduced
12317-436: The term gene , he explained his results in terms of discrete inherited units that give rise to observable physical characteristics. This description prefigured Wilhelm Johannsen 's distinction between genotype (the genetic material of an organism) and phenotype (the observable traits of that organism). Mendel was also the first to demonstrate independent assortment , the distinction between dominant and recessive traits,
12430-412: The term "gene" (inspired by the ancient Greek : γόνος, gonos , meaning offspring and procreation) and, in 1906, William Bateson , that of " genetics " while Eduard Strasburger , among others, still used the term "pangene" for the fundamental physical and functional unit of heredity. Advances in understanding genes and inheritance continued throughout the 20th century. Deoxyribonucleic acid (DNA)
12543-446: Was first suggested by Gregor Mendel (1822–1884). From 1857 to 1864, in Brno , Austrian Empire (today's Czech Republic), he studied inheritance patterns in 8000 common edible pea plants , tracking distinct traits from parent to offspring. He described these mathematically as 2 combinations where n is the number of differing characteristics in the original peas. Although he did not use
12656-406: Was proposed that a bivalent structure (with trimethylation of both lysine 4 and 27 on histone H3) is involved in early mammalian development. Another study tested the role of acetylation of histone 4 on lysine 16 on chromatin structure and found that homogeneous acetylation inhibited 30 nm chromatin formation and blocked adenosine triphosphate remodeling. This singular modification changed
12769-430: Was shown to be the molecular repository of genetic information by experiments in the 1940s to 1950s. The structure of DNA was studied by Rosalind Franklin and Maurice Wilkins using X-ray crystallography , which led James D. Watson and Francis Crick to publish a model of the double-stranded DNA molecule whose paired nucleotide bases indicated a compelling hypothesis for the mechanism of genetic replication. In
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