Histone H1

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linker histone H1 and H5 family
PBB Protein HIST1H1B image.jpg
PDB rendering of HIST1H1B based on 1ghc.
Identifiers
Symbol Linker_histone
Pfam PF00538
InterPro IPR005818
SMART SM00526
SCOP 1hst
SUPERFAMILY 1hst

Histone H1 is one of the five main histone protein families which are components of chromatin in eukaryotic cells. Though highly conserved, it is nevertheless the most variable histone in sequence across species.

Structure[edit]

A diagram showing where H1 can be found in the nucleosome

Metazoan H1 proteins feature a central globular 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.[1]

Function[edit]

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 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.[2] 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.[3][4][5]

It is uncertain whether H1 promotes a solenoid (DNA)-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.[6] Nuclease digestion and DNA footprinting experiments suggest that the globular domain of histone H1 localizes near the nucleosome dyad, where it protects approximately 15-30 base pairs of additional DNA.[7][8][9][10]

In addition, experiments on reconstituted chromatin reveal a characteristic stem motif at the dyad in the presence of H1.[11] 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 the tail binds to linker DNA and neutralizes its negative charge.[6][9]

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 the gene.[12][13][14] 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.[15][16] 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.[17][18][19]

Dynamics[edit]

A major surprise was the recent discovery from photobleaching experiments that linker histones to be a far more dynamic component of chromatin than core histones, with FRAP studies yielding a t50 of about 1 minute in somatic nuclei.[20][21]

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 is chromatin bound.[22] 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.[23]

Cytoplasmic factors appear to be necessary for the dynamic exchange of histone H1 on chromatin, but these have yet to be specifically identified.[24] 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 the affinity of H1 for chromosomes and therefore promote mitotic chromosome condensation (see Mitotic Phosphorylation by CDK1).[16]

Isoforms[edit]

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.[25][26][27] One isoform is histone H5, which is only found in avian erythrocytes, which unlike mammalian erythrocytes, 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.[27][28][29][30] Despite having more negative charges than somatic isoforms, H1M binds with higher affinity to mitotic chromosomes in Xenopus egg extracts.[16]

Mitotic Phosphorylation by CDK1[edit]

At mitosis, somatic H1 isoforms undergo phosphorylation at multiple cyclin-dependent kinase 1 (CDK1) consensus sites, which introduces multiple negative charges. Phosphorylation increases the affinity of H1 for mitotic chromosomes in Xenopus egg extracts and embryos, as determined by fluorescence recovery after photobleaching of wild-type H1 versus non-phosphorylable and phosphomimetic point mutants. These increases in binding affinity appear to offset the cytoplasmic dilution of H1 which occurs in mitotic cells following nuclear envelope breakdown, illustrating how the cell can regulate H1 to suit specific cellular conditions.[16]

See also[edit]

References[edit]

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  2. ^ Jeon, Kwang W.; Berezney, Ronald (1995). Structural and functional organization of the nuclear matrix. Boston: Academic Press. pp. 214–7. ISBN 0-12-364565-4. 
  3. ^ Finch JT, Klug A (June 1976). "Solenoidal model for superstructure in chromatin". Proc. Natl. Acad. Sci. U.S.A. 73 (6): 1897–901. doi:10.1073/pnas.73.6.1897. PMC 430414. PMID 1064861. 
  4. ^ Thoma F, Koller T (September 1977). "Influence of histone H1 on chromatin structure". Cell 12 (1): 101–7. doi:10.1016/0092-8674(77)90188-X. PMID 561660. 
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  6. ^ a b van Holde K, Zlatanova J (October 1996). "What determines the folding of the chromatin fiber?". Proc. Natl. Acad. Sci. U.S.A. 93 (20): 10548–55. doi:10.1073/pnas.93.20.10548. PMC 38190. PMID 8855215. 
  7. ^ Varshavsky AJ, Bakayev VV, Georgiev GP (February 1976). "Heterogeneity of chromatin subunits in vitro and location of histone H1". Nucleic Acids Res. 3 (2): 477–92. doi:10.1093/nar/3.2.477. PMC 342917. PMID 1257057. 
  8. ^ Whitlock JP, Simpson RT (July 1976). "Removal of histone H1 exposes a fifty base pair DNA segment between nucleosomes". Biochemistry 15 (15): 3307–14. doi:10.1021/bi00660a022. PMID 952859. 
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  10. ^ Staynov DZ, Crane-Robinson C (December 1988). "Footprinting of linker histones H5 and H1 on the nucleosome". EMBO J. 7 (12): 3685–91. PMC 454941. PMID 3208745. 
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  12. ^ Dworkin-Rastl E, Kandolf H, Smith RC (February 1994). "The maternal histone H1 variant, H1M (B4 protein), is the predominant H1 histone in Xenopus pregastrula embryos". Dev. Biol. 161 (2): 425–39. doi:10.1006/dbio.1994.1042. PMID 8313993. 
  13. ^ Brown DT, Alexander BT, Sittman DB (February 1996). "Differential effect of H1 variant overexpression on cell cycle progression and gene expression". Nucleic Acids Res. 24 (3): 486–93. doi:10.1093/nar/24.3.486. PMC 145659. PMID 8602362. 
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  15. ^ Maresca TJ, Freedman BS, Heald R (June 2005). "Histone H1 is essential for mitotic chromosome architecture and segregation in Xenopus laevis egg extracts". J. Cell Biol. 169 (6): 859–69. doi:10.1083/jcb.200503031. PMC 2171634. PMID 15967810. 
  16. ^ a b c d Freedman BS, Heald R (June 2010). "Functional Comparison of Linker Histones in Xenopus Reveals Isoform-Specific Regulation by Cdk1 and RanGTP". Curr. Biol. 20 (11): 1048–52. doi:10.1016/j.cub.2010.04.025. PMC 2902237. PMID 20471264. 
  17. ^ Shen X, Yu L, Weir JW, Gorovsky MA (July 1995). "Linker histones are not essential and affect chromatin condensation in vivo". Cell 82 (1): 47–56. doi:10.1016/0092-8674(95)90051-9. PMID 7606784. 
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  19. ^ Lu X, Wontakal SN, Emelyanov AV, Morcillo P, Konev AY, Fyodorov DV, Skoultchi AI (February 2009). "Linker histone H1 is essential for Drosophila development, the establishment of pericentric heterochromatin, and a normal polytene chromosome structure". Genes Dev. 23 (4): 452–65. doi:10.1101/gad.1749309. PMC 2648648. PMID 19196654. 
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  21. ^ Chen D, Dundr M, Wang C, Leung A, Lamond A, Misteli T, Huang S (January 2005). "Condensed mitotic chromatin is accessible to transcription factors and chromatin structural proteins". J. Cell Biol. 168 (1): 41–54. doi:10.1083/jcb.200407182. PMC 2171683. PMID 15623580. 
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  23. ^ Xiao, B.; Freedman, B. S.; Miller, K. E.; Heald, R.; Marko, J. F. (2012). "Histone H1 compacts DNA under force and during chromatin assembly". Molecular Biology of the Cell 23 (24): 4864–4871. doi:10.1091/mbc.E12-07-0518. PMC 3521692. PMID 23097493.  edit
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