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40-427: HMGN1 and HMGN2 (initially designated HMG-14 and HMG-17 respectively) were discovered by E.W. Johns research group in the early 1970s. HMGN3 , HMGN4 , and HMGN5 were discovered later and are less abundant. HMGNs are nucleosome binding proteins that help in transcription, replication, recombination, and DNA repair. They can also alter the chromatin epigenetic landscape, helping to stabilize cell identity. There

80-421: A critical component of neural differentiation and are elevated in neural stem cells (neural progenitor cells). For example, in a knock down study, loss of HMGN1,2&3 resulted in lower population of astrocyte cells and higher population of neural progenitor cells. In oligodendrocyte differentiation HMGNs are critical, since when HMGN1&2 are both knocked out the population of oligodendrocytes in spinal tissue

120-542: A full organism level. This resulted in the mice showing increasing sensitivity to UV radiation when having less than normal levels of HMGN(2). This would indicate that HMGN might facilitate repair of UV damage. The same increase in sensitivity was observed  in mice when exposed to gamma radiation, however the cellular processes that repair DNA in either case are drastically different, leading to an inconclusive state whether HMGN proteins facilitate DNA repair in vivo. HMGN1 and HMGN2 do not co-localize within living cells. This

160-414: A mobile character as they are continuously able to bind and unbind to nucleosomes depending on the intracellular environment and signaling. Active competition between HMGNs and H1 serve an active role in chromatin remodeling and as result play a role in the cell cycle and cellular differentiation where chromatin compaction and de-compaction determine if certain genes are expressed or not. Histone acetylation

200-486: A significant difference of a cell's total transcriptional activity. Several transcriptome studies have been conducted which show various other genes are either unregulated or down regulated due to HMGN absence. Interestingly in the case of HMGN1&2 only knocking out HMGN1 or HMGN2 results in changes for just few genes. But when you knock out both HMGN1&2 there is far more pronounced effect with regard to changes in gene activity. For example, in mice brain when only HMGN1

240-562: Is histone H5 , which is only found in avian erythrocytes , which are unlike mammalian erythrocytes in that they have nuclei . Another isoform is the oocyte/ zygotic H1M isoform (also known as B4 or H1foo), found in sea urchins, frogs, mice, and humans, which is replaced in the embryo by somatic isoforms H1A-E, and H10 which resembles H5. Despite having more negative charges than somatic isoforms, H1M binds with higher affinity to mitotic chromosomes in Xenopus egg extracts. Like other histones,

280-468: Is actually beneficial as the presence of at least one HMGN variant vastly improves tissue differentiation and development. These findings are summarized in the figure to the right. HMGN1 3150 15312 ENSG00000205581 ENSMUSG00000040681 P05114 P18608 NM_004965 NM_008251 NP_004956 NP_032277 Non-histone chromosomal protein HMG-14 is a protein that in humans

320-746: Is chromatin bound. H1 compacts and stabilizes DNA under force and during chromatin assembly, which suggests that dynamic binding of H1 may provide protection for DNA in situations where nucleosomes need to be removed. Cytoplasmic factors appear to be necessary for the dynamic exchange of histone H1 on chromatin, but these have yet to be specifically identified. H1 dynamics may be mediated to some degree by O-glycosylation and phosphorylation. O-glycosylation of H1 may promote chromatin condensation and compaction. Phosphorylation during interphase has been shown to decrease H1 affinity for chromatin and may promote chromatin decondensation and active transcription. However, during mitosis phosphorylation has been shown to increase

360-419: Is composed of HMGA, HMBG, and HMGN families. HMGA is associated with chromatin throughout the cell cycle, located in the scaffold of the metaphase chromosome. Both HMGB and HMGN are associated with the mitotic chromosome. The interactions of all HMGs with chromatin is highly dynamic, proteins move constantly throughout the nucleus. The sample nucleosomes for potential binding sites in a "stop and go" manner, with

400-475: Is elevated during initial stages of eye development in progenitor cells, but is decreased in newly formed and fated cells, such as lens fiber cells. HMGN2 in contrast stays elevated in both embryonic and adult eye cells. HMGN3 was found to be especially elevated at 2 weeks (for an adult mouse) in the inner nuclear and ganglion cells. This shows there is an uneven distribution of HMGNs in pre-fated and adult cells. In human brain development HMGNs have been shown to be

440-561: Is encoded by the HMGN1 gene . Chromosomal protein HMG14 and its close analog HMG17 (MIM 163910) bind to the inner side of the nucleosomal DNA , potentially altering the interaction between the DNA and the histone octamer . The 2 proteins may be involved in the process that maintains transcribable genes in a unique chromatin conformation. Their ubiquitous distribution and relative abundance, as well as

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480-445: Is heavily expressed as well as in adult pancreatic islet cells. It has been shown that the loss of HMGN3 in mice has led to a mild onset of diabetes due to ineffective insulin secretion. The discovery of HMGN4 was done by GenBank during a database search and identified it as a "new HMGN2 like transcript", indicating that HMGN4 is closely related to HMGN2. There has been very little research done on HMGN4 proteins. The gene associated with

520-496: Is indication of possible different roles of each HMGN. HMGN proteins are part of broader group of proteins referred to as High Mobility group chromosomal (HMG) proteins. This larger group was named this for their high electrophoretic mobility in polyacrylamide gels and is differentiated into 3 distinct but related groups, one of them being HMGN proteins. HMGN family can be further divided into specific proteins, these being HMGN1, HMGN2, HMGN3, HMGN4, and HMGN5.  The overall sizes of

560-424: Is larger than the previous HMGNs, containing 300+ amino acids, due to a long C-terminal domain that varies with species, explaining  why mice and humans have a different size of HMGN5. Its biological function is unknown but has shown expression in placental development. There have also been cases where HMGN5 was present in human tumors including, prostate cancer, breast cancer, lung cancer, etc. For this reason, it

600-447: Is nevertheless the most variable histone in sequence across species. Metazoan H1 proteins feature a central globular "winged helix" domain and long C- and short N-terminal tails. H1 is involved with the packing of the "beads on a string" sub-structures into a high order structure, whose details have not yet been solved. H1 found in protists and bacteria, otherwise known as nucleoproteins HC1 and HC2 ( Pfam PF07432 , PF07382 ), lack

640-430: Is not dependent on a functional HMGN nucleosomal binding domain, and weaker than the binding to interphase nucleosomes in which HMGNs form specific complexes with nucleosomes. Nucleosomes serve as the protein core (made from 8 histones) for DNA to wrap around, functioning as a foundation for the larger and more condensed chromatin structures of chromosomes. HMGN proteins compete with Histone H1 (linker histone not part of

680-569: Is still relatively little known about their structure and function. HMGN proteins are found in all vertebrates, and play a role in chromatin structure and histone modification. HMGNs come in long chains of amino acids, containing around 100 for HMGN1-4, and roughly 200 in HMGN5. Recent research on the HMGN family is focused on their effect on cell identity, and how reduction of HMGNs relates to induced reprogramming of mouse embryonic fibroblasts (MEFs). Much of

720-423: Is thought that HMGN5 might have some link to cancer and might be a potential target for cancer therapy in the future. The location of HMGN during mitosis is the subject of several studies. It is very difficult to date their intra-nuclear organization during the various stages of cell cycle. There is a superfamily of abundance and ubiquitous nuclear proteins that bind to chromatin without any known DNA sequence, which

760-495: Is uncertain whether H1 promotes a solenoid -like chromatin fiber, in which exposed linker DNA is shortened, or whether it merely promotes a change in the angle of adjacent nucleosomes, without affecting linker length However, linker histones have been demonstrated to drive the compaction of chromatin fibres that had been reconstituted in vitro using synthetic DNA arrays of the strong '601' nucleosome positioning element. Nuclease digestion and DNA footprinting experiments suggest that

800-426: Is usually associated with open chromatin, and histone methylation is usually associated with closed chromatin. With use of ChIP-sequencing it is possible to study DNA paired with proteins to determine what kind of histone modifications are present when the nucleosomes are bound to either H1 or HMGNs. Using this method it was found that H1 presence corresponded to high levels of H3K27me3 and H3K4me3, which means that

840-416: The "stop" step being longer than the "go" step. Through the use of immunofluorescence studies, live cell imaging, gel mobility shift assays, and bimolecular fluorescence complementation, the above was determined and also by comparing the chromatin binding properties of wild-type and HMGN mutant proteins. In conclusion, HMGNs can associate with mitotic chromatin. However, the binding of HMGN to mitotic chromatin

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880-487: The H3 histone is heavily methylated suggesting that the chromatin structure is closed. It was also found that HMGN presence corresponded to high levels of H3K27ac and H3K4me1 , conversely meaning that the H3 histone methylation is greatly reduced suggesting the chromatin structure is open. While the role of HMGNs are still being researched, it is clear that the absence of HMGNs in knock out (KO) and knock down (KD) studies result in

920-509: The HMGN1 and HMGN2 proteins, both forms of HMGN3 tend to be tissue and development specific. They are only expressed in certain tissues at specific developmental stages. There is no preference to a certain tissue given by the two variants of the HMGN3 proteins. There is equal likelihood that either be present in a certain highly expressed HMGN3 tissue. The brain and the eyes in particular are areas that HMGN3

960-510: The affinity of H1 for chromosomes and therefore promote mitotic chromosome condensation. The H1 family in animals includes multiple H1 isoforms that can be expressed in different or overlapping tissues and developmental stages within a single organism. The reason for these multiple isoforms remains unclear, but both their evolutionary conservation from sea urchin to humans as well as significant differences in their amino acid sequences suggest that they are not functionally equivalent. One isoform

1000-464: The brain, thymus, liver, and spleen suggesting HMGN variants also have specialized roles in addition to their overlapping functionality. This overlapping functionality may seem redundant or even deleterious, however these proteins are integral to various cellular processes, especially differentiation and embryogenesis as it provides a means for dynamic chromatin modeling. For example, in mice embryo, during ocular development HMGN1,2&3. HMGN1 expression

1040-520: The central domain and the N-terminal tail. H1 is less conserved than core histones. The globular domain is the most conserved part of H1. Unlike the other histones, H1 does not make up the nucleosome "bead". Instead, it sits on top of the structure, keeping in place the DNA that has wrapped around the nucleosome. H1 is present in half the amount of the other four histones, which contribute two molecules to each nucleosome bead. In addition to binding to

1080-410: The core nucleosome) for nucleosome binding sites. Once occupied one protein cannot displace the other. However both proteins are not permanently associated to the nucleosomes and can be removed via post transcriptional modifications. In the case of HMGN proteins, Protein kinase C (PKC) can phosphorylate the serine amino acids in the nucleosome binding domain present in all HMGN variants. This gives HMGNs

1120-740: The gene. In Xenopus egg extracts, linker histone depletion causes ~2-fold lengthwise extension of mitotic chromosomes, while overexpression causes chromosomes to hypercompact into an inseparable mass. Complete knockout of H1 in vivo has not been achieved in multicellular organisms due to the existence of multiple isoforms that may be present in several gene clusters, but various linker histone isoforms have been depleted to varying degrees in Tetrahymena , C. elegans, Arabidopsis, fruit fly, and mouse, resulting in various organism-specific defects in nuclear morphology, chromatin structure, DNA methylation, and/or specific gene expression. While most histone H1 in

1160-472: The globular domain of histone H1 localizes near the nucleosome dyad, where it protects approximately 15-30 base pairs of additional DNA. In addition, experiments on reconstituted chromatin reveal a characteristic stem motif at the dyad in the presence of H1. Despite gaps in our understanding, a general model has emerged wherein H1's globular domain closes the nucleosome by crosslinking incoming and outgoing DNA, while

1200-543: The high evolutionary conservation of the DNA-binding domain of the HMG14 family of proteins, suggest that they may be involved in an important cellular function. HMGN1 has been shown to interact with YWHAZ . This protein -related article is a stub . You can help Misplaced Pages by expanding it . Histone H1 Histone H1 is one of the five main histone protein families which are components of chromatin in eukaryotic cells. Though highly conserved , it

1240-479: The nucleosome, the H1 protein binds to the "linker DNA" (approximately 20-80 nucleotides in length) region between nucleosomes, helping stabilize the zig-zagged 30 nm chromatin fiber. Much has been learned about histone H1 from studies on purified chromatin fibers. Ionic extraction of linker histones from native or reconstituted chromatin promotes its unfolding under hypotonic conditions from fibers of 30 nm width to beads-on-a-string nucleosome arrays. It

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1280-432: The nucleus is bound to chromatin, H1 molecules shuttle between chromatin regions at a fairly high rate. It is difficult to understand how such a dynamic protein could be a structural component of chromatin, but it has been suggested that the steady-state equilibrium within the nucleus still strongly favors association between H1 and chromatin, meaning that despite its dynamics, the vast majority of H1 at any given timepoint

1320-449: The production of the HMGN4 is located in a region associated with schizophrenia on chromosome 6. Until this point every kind of HMGN has been identified in the vertebrates, but HMGN4 has only been seen and identified in primates. Within humans, HMGN4 has shown high levels of expression in the thyroid, thymus and the lymph nodes. The most recent addition to the HMGN protein family is of HMGN5. It

1360-409: The proteins targets the main elements that are responsible for the compactions of the chromatin. These have an expression rates that correlate to the differentiation of the cells it is present in. Areas that have experienced differentiation have reduced expression levels in comparison to undifferentiated areas, where HMGN1 and HMGN2 are highly expressed. HMGN3 has two variants, HMGN3a and HMGN3b. Unlike

1400-411: The proteins vary to each specific one, but HMGN1-4 average 100 amino acids. Whereas the larger HMGN5 proteins are 300+ amino acids long in mice and roughly 200 in length for humans. HMGN1 and HMGN2 are among the most common of the HMGN proteins. The main purpose and function are reducing the compaction of the cellular chromatin by nucleosome binding. NMR evidence shows that reducing compaction occurs when

1440-441: The research that has been done HMGN proteins have been done in vitro, while there is relatively little on the in vivo function and roles of HMGN proteins. Due to these proteins being predominantly found in higher eukaryotes, the use of microorganisms and other lower eukaryotes has deemed insufficient to determine the in vivo roles of HMGN proteins. A study was done with knockout mice to see the effect if any that HMGN proteins play on

1480-409: The same thing. They have largely the same affinity for nucleosomal binding sites. That means a lot of times if HMGN1 is absent, HMGN2 can fill in and vis versa. Using ChIP-seq it was found in mice chromosomes there were 16.5K sites were both HMGN1&2 could bind, 14.6K sites that had HMGN1 preference and only 6.4K sites that had HMGN2 preference. Differences in HMGN1 and HMGN2 activity are pronounced in

1520-440: The tail binds to linker DNA and neutralizes its negative charge. Many experiments addressing H1 function have been performed on purified, processed chromatin under low-salt conditions, but H1's role in vivo is less certain. Cellular studies have shown that overexpression of H1 can cause aberrant nuclear morphology and chromatin structure, and that H1 can serve as both a positive and negative regulator of transcription, depending on

1560-515: Was knocked out only 1 gene was up-regulated, when only HMGN2 was knocked out 19 genes were up-regulated and 29 down-regulated. But when both HMGN1&2 are knocked out 50 genes were up-regulated and 41 down-regulated. If you simply tallied the totals for the HMGN1 and HMGN2 knock outs you would not get the same results as an HMGN1&2 DKO (double knock out). This is described as functional compensation since both HMGN1 and HMGN2 are only slightly different in terms of protein structure and essentially do

1600-477: Was reduced 65%. However, due to functional compensation this effect is not observed when only HMGN1 or HMGN2 are knocked. This observation if not just correlation. With ChIP-seq analysis it is shown that chromatin modeling at the OLIG1&;2 genes (transcription factors involved in oligodendrocyte differentiation) is in an open conformation and has HMGNs bound to the nucleosomes. It can be inferred that this redundancy

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