Alternative titles; symbols
HGNC Approved Gene Symbol: H2BC1
Cytogenetic location: 6p22.2 Genomic coordinates (GRCh38): 6:25,726,777-25,727,345 (from NCBI)
The nucleosome is the basic 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, H3 (see 602810), and H4 (see 602822), around which DNA is wrapped. A fifth histone, histone H1 (see 142709), is bound to the linker DNA between nucleosomes and is important for the higher order structure of chromatin. HIST1H2BA is a core histone H2B (summary by Marzluff et al. (2002) and Foster and Downs (2005)).
For additional background information on histones, histone gene clusters, and the H2B histone family, see GENE FAMILY below.
All core histones contain a histone fold domain, which is central to the nucleosome core structure, and a flexible N-terminal domain that protrudes from the nucleosome core particle. H2A and H2B histones are unique in that they also have significant sequence on the C-terminal side of the histone fold. The H2B C-terminal domain forms an alpha helix and lies along the nucleosome. Like other histones, H2B histones can be subgrouped according to their temporal expression. Replication-dependent histones, such as HIST1H2BA through HIST1H2BO (602808), HIST2H2BE (601831), and HIST3H2BB, are mainly expressed during S phase. In contrast, replication-independent histones, or replacement variant histones, can be expressed throughout the cell cycle. Most replication-dependent H2B 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, and each contains at least 1 replication-dependent H2B histone gene. 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 (summary by Marzluff et al. (2002) and Foster and Downs (2005)).
By sequencing histones purified from human sperm, followed by database analysis, Zalensky et al. (2002) identified HIST1H2BA, which they called TSH2B. The deduced 127-amino acid protein shares 85% identity with somatic H2B.1 (see 602803), but it has more potential phosphorylation and myristoylation sites. TSH2B shares 95% and 93% amino acid identity with mouse and rat Tsh2b, respectively. RT-PCR detected TSH2B expression exclusively in testis. Using several extraction procedures, Zalensky et al. (2002) found that TSH2B was relatively tightly bound to sperm chromatin. Immunolocalization detected TSH2B in a punctate localization in mature sperm, but it was not part of the telomere-binding complex.
By genomic sequence analysis, Marzluff et al. (2002) identified the mouse and human HIST1H2BA genes. They noted that the HIST1H2BA protein in both mouse and human diverges from the H2B consensus sequence more significantly than other H2B family members.
By genomic sequence analysis, Zalensky et al. (2002) mapped the HIST1H2BA gene to chromosome 6.
By genomic sequence analysis, Marzluff et al. (2002) determined that the HIST1 cluster on chromosome 6p22-p21 contains 55 histone genes, including 15 H2B genes. The HIST1H2BA gene is the most telomeric H2B gene within the HIST1 cluster. 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, including 1 H2B gene (HIST2H2BE; 601831), and the HIST3 cluster on chromosome 1q42 contains 3 histone genes, including 1 H2B gene (HIST3H2BB). Hist2 and Hist3 are located on mouse chromosomes 3F1-F2 and 11B2, respectively. Marzluff et al. (2002) noted that all 3 histone clusters in human and mouse contain pairs of H2A and H2B genes. These paired H2A and H2B genes are transcribed from opposite strands, with their 5-prime ends separated by an intergenic region of less than 300 nucleotides. A similar organization of H2a and H2b genes is found in yeast, Drosophila, C. elegans, and sea urchin.
H2B Histone Family
The Ran GTPase (601179) controls nucleocytoplasmic transport, mitotic spindle formation, and nuclear envelope assembly. These functions rely on the association of the Ran-specific exchange factor, RCC1 (179710), with chromatin. Nemergut et al. (2001) found that RCC1 binds directly to mononucleosomes and to histones H2A and H2B. RCC1 utilizes these histones to bind Xenopus sperm chromatin, and the binding of RCC1 to nucleosomes or histones stimulates the catalytic activity of RCC1. Nemergut et al. (2001) proposed that the docking of RCC1 to H2A/H2B establishes the polarity of the Ran-GTP gradient that drives nuclear envelope assembly, nuclear transport, and other nuclear events.
Dorigo et al. (2004) analyzed compacted nucleosome arrays stabilized by introduction of disulfide crosslinks and showed that the chromatin fiber comprises 2 stacks of nucleosomes in accord with a 2-start model.
Kaposi sarcoma-associated herpesvirus (KSHV) latency-associated nuclear antigen (LANA) mediates viral genome attachment to mitotic chromosomes. Barbera et al. (2006) found that N-terminal LANA docks onto chromosomes by binding nucleosomes through the folded region of histones H2A-H2B. The same LANA residues were required for both H2A-H2B binding and chromosome association. Further, LANA did not bind Xenopus sperm chromatin, which is deficient in H2A-H2B; chromatin binding was rescued after assembly of nucleosomes containing H2A-H2B. Barbera et al. (2006) also described a 2.9-angstrom crystal structure of a nucleosome complexed with the first 23 LANA amino acids. The LANA peptide forms a hairpin that interacts exclusively with an acidic H2A-H2B region that is implicated in the formation of higher order chromatin structure. Barbera et al. (2006) concluded that their findings presented a paradigm for how nucleosomes may serve as binding platforms for viral and cellular proteins and revealed a previously unknown mechanism for KSHV latency.
Using a reconstituted chromatin-transcription system, Pavri et al. (2006) showed that elongation by RNA polymerase II (see 180660) through the nucleosomal barrier was minimally dependent on FACT (see 604328), PAF (see 610506), and monoubiquitination of H2B at lys120.
Bungard et al. (2010) found that AMPK (see 602739) activates transcription through direct association with chromatin and phosphorylation of histone H2B at ser36. AMPK recruitment and H2B ser36 phosphorylation colocalized within genes activated by AMPK-dependent pathways, both in promoters and in transcribed regions. Ectopic expression of H2B in which ser36 was substituted by alanine reduced transcription and RNA polymerase II association to AMPK-dependent genes, and lowered cell survival in response to stress. Bungard et al. (2010) concluded that their results placed AMPK-dependent H2B serine-36 phosphorylation in a direct transcriptional and chromatin regulatory pathway leading to cellular adaptation to stress.
Fujiki et al. (2011) reported that histone H2B is acylated by O-linked N-acetylglucosamine (GlcNAcylated) at residue S112 by O-GlcNAc transferase (OGT; 300255) in vitro and in living cells. Histone GlcNAcylation fluctuated in response to extracellular glucose through the hexosamine biosynthesis pathway. H2B S112 GlcNAcylation promotes K120 monoubiquitination, in which the GlcNAc moiety can serve as an anchor for a histone H2B ubiquitin ligase. H2B S112 GlcNAc was localized to euchromatic areas on fly polytene chromosomes. In a genomewide analysis, H2B S112 GlcNAcylation sites were observed widely distributed over chromosomes including transcribed gene loci, with some sites colocalizing with H2B K120 monoubiquitination. Fujiki et al. (2011) concluded that H2B S112 GlcNAcylation is a histone modification that facilitates H2BK120 monoubiquitination, presumably for transcriptional activation.
Reviews
Wyrick and Parra (2009) reviewed the role of H2A and H2B posttranslational modifications in transcription.
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 H2A, H2B, H3, and H4 genes were named systematically according to their location within the HIST1, HIST2, and HIST3 clusters. For example, HIST1H2BA is the most telomeric H2B gene within HIST1, and HIST1H2BO (602808) is the most centromeric. In contrast, the H1 genes, all of which are located within HIST1, were named according to their mouse homologs. Thus, HIST1H1A (142709) is homologous to mouse H1a, HIST1H1B (142711) is homologous to mouse H1b, and so on.
Maile et al. (2004) reported that serine-33 of histone H2B (H2B-S33) is a physiologic substrate for the TAF1 (313650) C-terminal kinase domain (CTK) and that H2B-S33 phosphorylation is essential for transcriptional activation events that promote cell cycle progression and development. Because of image manipulation that rendered the data, results, and conclusions not reliable, the journal Science retracted the paper of Maile et al. (2004) at the request of the University of California, Riverside and Dr. Frank Sauer.
Barbera, A. J., Chodaparambil, J. V., Kelley-Clarke, B., Joukov, V., Walter, J. C., Luger, K., Kaye, K. M. The nucleosomal surface as a docking station for Kaposi's sarcoma herpesvirus LANA. Science 311: 856-861, 2006. [PubMed: 16469929] [Full Text: https://doi.org/10.1126/science.1120541]
Bungard, D., Fuerth, B. J., Zeng, P.-Y., Faubert, B., Maas, N. L., Viollet, B., Carling, D., Thompson, C. B., Jones, R. G., Berger, S. L. Signaling kinase AMPK activates stress-promoted transcription via histone H2B phosphorylation. Science 329: 1201-1205, 2010. [PubMed: 20647423] [Full Text: https://doi.org/10.1126/science.1191241]
Dorigo, B., Schalch, T., Kulangara, A., Duda, S., Schroeder, R. R., Richmond, T. J. Nucleosome arrays reveal the two-start organization of the chromatin fiber. Science 306: 1571-1573, 2004. [PubMed: 15567867] [Full Text: https://doi.org/10.1126/science.1103124]
Foster, E. R., Downs, J. A. Histone H2A phosphorylation in DNA double-strand break repair. FEBS J. 272: 3231-3240, 2005. [PubMed: 15978030] [Full Text: https://doi.org/10.1111/j.1742-4658.2005.04741.x]
Fujiki, R., Hashiba, W., Sekine, H., Yokoyama, A., Chikanishi, T., Ito, S., Imai, Y., Kim, J., He, H. H., Igarashi, K., Kanno, J., Ohtake, F., Kitagawa, H., Roeder, R. G., Brown, M., Kato, S. GlcNAcylation of histone H2B facilitates its monoubiquitination. Nature 480: 557-560, 2011. [PubMed: 22121020] [Full Text: https://doi.org/10.1038/nature10656]
Maile, T., Kwoczynski, S., Katzenberger, R. J., Wassarman, D. A., Sauer, F. TAF1 activates transcription by phosphorylation of serine 33 in histone H2B. Science 304: 1010-1014, 2004. Note: Retraction: Science 344: 981 only, 2014. [PubMed: 15143281] [Full Text: https://doi.org/10.1126/science.1095001]
Marzluff, W. F., Gongidi, P., Woods, K. R., Jin, J., Maltais, L. J. The human and mouse replication-dependent histone genes. Genomics 80: 487-498, 2002. [PubMed: 12408966]
Nemergut, M. E., Mizzen, C. A., Stukenberg, T., Allis, C. D., Macara, I. G. Chromatin docking and exchange activity enhancement of RCC1 by histones H2A and H2B. Science 292: 1540-1543, 2001. [PubMed: 11375490] [Full Text: https://doi.org/10.1126/science.292.5521.1540]
Pavri, R., Zhu, B., Li, G., Trojer, P., Mandal, S., Shilatifard, A., Reinberg, D. Histone H2B monoubiquitination functions cooperatively with FACT to regulate elongation by RNA polymerase II. Cell 125: 703-717, 2006. [PubMed: 16713563] [Full Text: https://doi.org/10.1016/j.cell.2006.04.029]
Wyrick, J. J., Parra, M. A. The role of histone H2A and H2B post-translational modifications in transcription: a genomic perspective. Biochim. Biophys. Acta 1789: 37-44, 2009. [PubMed: 18675384] [Full Text: https://doi.org/10.1016/j.bbagrm.2008.07.001]
Zalensky, A. O., Siino, J. S., Gineitis, A. A., Zalenskaya, I. A., Tomilin, N. V., Yau, P., Bradbury, E. M. Human testis/sperm-specific histone H2B (hTSH2B): molecular cloning and characterization. J. Biol. Chem. 277: 43474-43480, 2002. [PubMed: 12213818] [Full Text: https://doi.org/10.1074/jbc.M206065200]