Alternative titles; symbols
HGNC Approved Gene Symbol: H1-1
Cytogenetic location: 6p22.2 Genomic coordinates (GRCh38): 6:26,017,032-26,017,787 (from NCBI)
The nucleosome is the fundamental repeat unit of eukaryotic chromatin. The nucleosome core particle consists of an octamer formed by 2 each of the core histones H2A (see 613499), H2B (see 609904), H3 (see 602810), and H4 (see 602822), around which DNA is wrapped. A fifth histone, the linker H1 histone, completes the nucleosome by interacting with DNA entering and exiting the nucleosome core particle. H1 histones, such as HIST1H1A, are involved in the formation of higher order chromatin structures, and they modulate the accessibility of regulatory proteins, chromatin-remodeling factors, and histone modification enzymes to their target sites (reviewed by Izzo et al. (2008) and Happel and Doenecke (2009)).
For additional background information on histones, histone gene clusters, and the H1 histone family, see GENE FAMILY below.
The H1 histone family is the most divergent class of histones, with at least 11 different H1 histones present in humans. H1 histones have a tripartite structure that consists of a short N-terminal domain enriched in basic amino acids, a central conserved globular domain involved in DNA binding, and a long C-terminal tail enriched in lysine, serine, and proline. Like other histones, H1 histones can be subgrouped according to their temporal expression. Replication-dependent histones, such as H1.1 through H1.5 (HIST1HB; 142711) and H1T (HIST1H1T; 142712), are mainly expressed during S phase. In contrast, replication-independent histones, or replacement histones, such as H1.0 (H1F0; 142708), H1T2 (H1FNT), H1OO (H1FOO), H1X (H1FX; 602785), and HILS1 (608101), are expressed throughout the cell cycle. All replication-dependent H1 histone genes, as well as other core histone genes, are located within histone gene cluster-1 (HIST1) on chromosome 6p22-p21. Two other histone gene clusters, HIST2 and HIST3, are located on chromosomes 1q21 and 1q42, respectively, but they are devoid of H1 genes. In mouse, the Hist1, Hist2, and Hist3 gene clusters are located on chromosomes 13A2-A3, 3F1-F2, and 11B2, respectively. All replication-dependent histone genes are intronless, and they encode mRNAs that lack a poly(A) tail, ending instead in a conserved stem-loop sequence. Unlike replication-dependent histone genes, replication-independent histone genes are solitary genes that are located on chromosomes apart from any other H1 or core histone genes. Some replication-independent histone genes contain introns and encode mRNAs with poly(A) tails. H1 histones, as well as core histones, can also be subgrouped based on their spatial expression. Somatic H1 histones (H1.1 through H1.5 and H1X) are expressed ubiquitously, whereas other H1 histones are expressed mainly in terminally differentiated cells (H1.0) or in germ cells (H1T, H1T2, H1OO, and HILS1) (summary by Marzluff et al. (2002), Izzo et al. (2008), and Happel and Doenecke (2009)).
Eick et al. (1989) cloned the genes encoding H1.1 and H1.2 (HIST1H1C; 142710).
Using Northern blot analysis, Burfeind et al. (1994) found that the H1.1 gene was expressed in testis and thymus, but not in other human tissues. In testis, it was restricted to early round spermatids that belonged to the fraction of postmeiotic sperm cells. Burfeind et al. (1994) found that the H1.1 gene is highly conserved in higher primates, whereas no cross-hybridization could be detected with DNA from other mammalian species, such as mouse, rat, hamster, and bull.
Histone H1 functions in the compaction of chromatin into higher order structures derived from the repeating 'beads-on-a-string' nucleosome polymer. Modulation of H1 binding activity is thought to be an important step in the potentiation/depotentiation of chromatin structure for transcription. It is generally accepted that H1 binds less tightly than other histones to DNA in chromatin and can readily exchange in living cells. Fusion proteins of histone H1 and green fluorescent protein (GFP) have been shown to associate with chromatin in an apparently identical fashion to native histone H1, providing a means by which to study histone H1-chromatin interactions in living cells. Lever et al. (2000) used human cells with a stably integrated H1.1-GFP fusion protein to monitor histone H1 movement directly by fluorescence recovery after photobleaching in living cells. They found that exchange is rapid in both condensed and decondensed chromatin, occurs throughout the cell cycle, and does not require fiber-fiber interactions. Treatment with drugs that alter protein phosphorylation significantly reduced exchange rates. Lever et al. (2000) concluded that histone H1 exchange in vivo is rapid, occurs through a soluble intermediate, and is modulated by the phosphorylation of a protein or proteins as yet to be determined.
Using techniques similar to those of Lever et al. (2000), Misteli et al. (2000) showed that almost the entire population of H1-GFP is bound to chromatin at any 1 time; however, H1-GFP is exchanged continuously between chromatin regions. The residence time of H1-GFP on chromatin between exchange events is several minutes in both euchromatin and heterochromatin. In addition to the mobile fraction, Misteli et al. (2000) detected a kinetically distinct, less mobile fraction. After hyperacetylation of core histones, the residence time of H1-GFP was reduced, suggesting a higher rate of exchange upon chromatin remodeling. Misteli et al. (2000) concluded that their results support a model in which linker histones bind dynamically to chromatin in a stop-and-go mode.
Hizume et al. (2005) noted that addition of histone H1 to reconstituted nucleosomes represses transcriptional activity and prevents sliding of core histones along DNA. They used nucleosome core particles and histone H1 purified from HeLa cells for in vitro nucleosome reconstitution assays. Under optimal salt concentrations, nucleosome core particles alone formed beads-on-a-string chromatin fibers on plasmid DNA. However, addition of purified histone H1 induced higher order folding in a concentration-dependent manner. Hizume et al. (2005) proposed a model of chromatin fiber formation where fiber compaction is dependent on both the local salt environment and histone H1 availability.
Krishnakumar et al. (2008) used genomic and gene-specific approaches to show that 2 factors, histone H1 and PARP1 (173870), exhibit a reciprocal pattern of chromatin binding at many RNA polymerase II-transcribed promoters. PARP1 was enriched and H1 was depleted at these promoters. This pattern of binding was associated with actively transcribed genes. Furthermore, Krishnakumar et al. (2008) showed that PARP1 acts to exclude H1 from a subset of PARP1-stimulated promoters, suggesting a functional interplay between PARP1 and H1 at the level of nucleosome binding. Krishnakumar et al. (2008) concluded that although H1 and PARP1 have similar nucleosome-binding properties and effects on chromatin structure in vitro, they have distinct roles in determining gene expression in vivo.
Reviews
Doenecke et al. (1994) reviewed the organization and expression of H1 histone and H1 replacement histone genes.
Izzo et al. (2008) reviewed the H1 histone family and discussed specific roles of H1 proteins that challenged the concept of H1 being a mere structural component of chromatin and a general repressor of transcription.
Happel and Doenecke (2009) reviewed the structural and functional aspects of H1 histones, with an emphasis on the structural role and impact of H1 histones on the functional state of chromatin.
By PCR analysis of chromosomal DNA from a panel of human/rodent somatic cell hybrids, Albig et al. (1993) found that 5 human H1 histone genes, H1.1 through H1.5, and the gene encoding the testis-specific H1T subtype are located on chromosome 6. They found that the H1.0 subtype, which is not neighbored by core histone genes, maps to chromosome 22. By fluorescence in situ hybridization with human metaphase chromosomes and PCR analysis of somatic cell hybrid DNAs carrying only fragments of chromosome 6, they demonstrated that the histone genes are clustered in the 6p22.2-p21.1 region.
By PCR analysis of human/rodent cell hybrid DNAs, Burfeind et al. (1994) confirmed the localization of histone H1.1 to chromosome 6 and by radioactive in situ hybridization regionalized the locus to 6p21.3.
Through detailed localization of the H1 histone genes with radiation hybrids and long range pulsed field gel electrophoresis, Volz et al. (1997) found that the histone genes on the short arm of chromosome 6 are organized into 2 clusters. The major cluster at 6p22-p21.3 contains 32 histone genes, including the H1 genes H1.1, H1.2, H1.3 (HIST1H1D; 142210), H1.4 (HIST1H1E; 142220), and H1T, numerous core histone genes, and the HFE gene (613609).
By analysis of a YAC contig, Albig et al. (1997) mapped the H1.1 gene to chromosome 6p21.3 within a cluster of 35 histone genes, including H1.1 to H1.4 and H1T. They found that the H1.5 gene is located in a second cluster on 6p about 2 Mb centromeric of the major cluster. In a contig of the histone gene-containing cosmids from this second cluster on chromosome 6p, Albig and Doenecke (1997) found 1 H1 gene (H1.5), 5 H2A genes, 4 H2B genes, 1 H2B pseudogene, 3 H3 genes, 3 H4 genes, and 1 H4 pseudogene. The cluster extends about 80 kb with a nonordered arrangement of the histone genes. The dinucleotide repeat polymorphic marker D6S105 was localized at the telomeric end of this histone gene cluster. Almost all human histone genes isolated to that time had been localized within the 2 clusters on 6p or in a small group of histone genes on chromosome 1.
Albig and Doenecke (1997) reviewed the organization of histone genes in mouse. Both the human and mouse histone gene clusters are found on 2 chromosomes and have nearly the same composition and number of genes. The 2 histone gene clusters on human chromosome 6p correspond to 2 clusters located on mouse chromosome 13. The relative localization of the histone H1 and H3 genes appears to be highly conserved. The 2 clusters are 0.6 Mb apart in mouse and 2 Mb apart in human. A third cluster of mouse histone genes on chromosome 3 corresponds to the group of human genes located on chromosome 1. The authors stated that, to that time, a total of 55 clustered histone genes had been identified in mouse. Albig and Doenecke (1997) gave a pictorial representation of the mapping of the other histone genes as well as a tabular summary of human histone gene sequences deposited in the EMBL nucleotide sequence database.
By genomic sequence analysis, Marzluff et al. (2002) determined that the HIST1 cluster on chromosome 6p22-p21 contains 55 histone genes, including all 6 replication-dependent H1 genes. The HIST1 cluster spans over 2 Mb and includes 2 large gaps (over 250 kb each) where there are no histone genes, but many other genes. The organization of histone genes in the mouse Hist1 cluster on chromosome 13A2-A3 is essentially identical to that in human HIST1. The HIST2 cluster on chromosome 1q21 contains 6 histone genes, and the HIST3 cluster on chromosome 1q42 contains 3 histone genes. Hist2 and Hist3 are located on mouse chromosomes 3F1-F2 and 11B2, respectively.
Marzluff et al. (2002) provided a nomenclature for replication-dependent histone genes located within the HIST1, HIST2, and HIST3 clusters. The symbols for these genes all begin with HIST1, HIST2, or HIST3 according to which cluster they are located in. The H1 genes, all of which are located within HIST1, were named according to their mouse homologs. Thus, HIST1H1A is homologous to mouse H1a, HIST1H1B is homologous to mouse H1b, and so on. In contrast, the H2A, H2B, H3, and H4 genes were named systematically according to their location within the HIST1, HIST2, and HIST3 clusters. For example, HIST1H4A (602822) is the most telomeric H4 gene within HIST1, and HIST1H4L (602831) is the most centromeric.
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Hardin, J. A., Thomas, J. O. Antibodies to histones in systemic lupus erythematosus: localization of prominent autoantigens on histones H1 and H2B. Proc. Nat. Acad. Sci. 80: 7410-7414, 1983. [PubMed: 6584863] [Full Text: https://doi.org/10.1073/pnas.80.24.7410]
Hizume, K., Yoshimura, S. H., Takeyasu, K. Linker histone H1 per se can induce three-dimensional folding of chromatin fiber. Biochemistry 44: 12978-12989, 2005. [PubMed: 16185066] [Full Text: https://doi.org/10.1021/bi050623v]
Izzo, A., Kamieniarz, K., Schneider, R. The histone H1 family: specific members, specific functions? Biol. Chem. 389: 333-343, 2008. [PubMed: 18208346] [Full Text: https://doi.org/10.1515/BC.2008.037]
Krishnakumar, R., Gamble, M. J., Frizzell, K. M., Berrocal, J. G., Kininis, M., Kraus, W. L. Reciprocal binding of PARP-1 and histone H1 at promoters specifies transcriptional outcomes. Science 319: 819-821, 2008. [PubMed: 18258916] [Full Text: https://doi.org/10.1126/science.1149250]
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Misteli, T., Gunjan, A., Hock, R., Bustin, M., Brown, D. T. Dynamic binding of histone H1 to chromatin in living cells. Nature 408: 877-881, 2000. [PubMed: 11130729] [Full Text: https://doi.org/10.1038/35048610]
Volz, A., Albig, W., Doenecke, D., Ziegler, A. Physical mapping of the region around the large histone gene cluster on human chromosome 6p22.2. DNA Seq. 8: 173-180, 1997. [PubMed: 10668964] [Full Text: https://doi.org/10.3109/10425179709034070]