Alternative titles; symbols
HGNC Approved Gene Symbol: HIRA
Cytogenetic location: 22q11.21 Genomic coordinates (GRCh38): 22:19,330,698-19,431,733 (from NCBI)
The human TUPLE1 gene encodes a putative transcription regulator with a sequence similar to that of the yeast TUP1 gene (Halford et al., 1993). The protein product of the TUPLE1 gene contains WD40 domains, motifs thought to be involved in protein-protein interactions. Halford et al. (1993) found that the TUPLE1 gene is expressed in a range of fetal tissues. Halford et al. (1993) cloned the murine Tuple1 gene and showed that it has strong sequence similarity to the human gene.
Lamour et al. (1995) isolated a cDNA that encodes a protein of 1,017 amino acids, designated HIRA on the basis of its homology to the HIR1 and HIR2 transcriptional repressors of S. cerevisiae. HIRA encompasses the entire TUPLE1 protein with an additional 207 internal amino acid residues and an extra 44 N-terminal residues, a result of an alternative start codon. Thus, TUPLE1 cDNA appears to represent a truncated version of the HIRA cDNA.
Roberts et al. (1997) cloned the chick homolog of Hira and conducted in situ expression analysis in early chick embryos. Hira is expressed in the developing neural plate, the neural tube, the neural crest, and the mesenchyme of the head and branchial arch structures. From these findings, the authors suggested that HIRA may have a role in the haploinsufficiency syndromes caused by deletion of 22q11.
Wilming et al. (1997) isolated several murine embryonic cDNA homologs of the DGS candidate gene HIRA. They identified several alternatively spliced transcripts. Sequence analysis revealed that Hira bears homology to the p60 subunit of the human chromatin assembly factor I (CAF1A; 601245) and 2 yeast proteins, suggesting that Hira may have some role in chromatin assembly and/or histone regulation. Whole-mount in situ hybridization of mouse embryos at various stages of development showed that Hira is ubiquitously expressed. However, high levels of transcripts were detected in the cranial neural folds, frontonasal mass, first 2 pharyngeal arches, circumpharyngeal neural crest, and limb buds. Since many of the structures affected in DiGeorge syndrome derive from these HIRA-expressing cell populations, Wilming et al. (1997) proposed that haploinsufficiency of HIRA contributes to at least some of the features of the DGS phenotype.
Magnaghi et al. (1998) reported an interaction between HIRA and the transcription factor PAX3 (606597). PAX3 haploinsufficiency results in the mouse 'splotch' and human Waardenburg syndrome (see 193500) phenotypes. Mice homozygous for PAX3 mutations die in utero with a phenocopy of DiGeorge syndrome, or neonatally with neural tube defects. HIRA was also found to interact with core histones. Thus, altered stoichiometry of complexes containing HIRA may be important for the development of structures affected in Waardenburg syndrome and DiGeorge syndrome.
By Western blot analysis and immunofluorescence, Lorain et al. (1998) found that HIRA is localized in the nucleus of human cells. Using a yeast 2-hybrid screen with HIRA as bait, these authors identified HeLa cell cDNAs encoding 4 HIRA-interacting proteins, or HIRIPs. HIRIP1 and HIRIP2 are members of the H2B core histone family. In vitro assays revealed that HIRA bound directly to core histones H2B and H4, using overlapping but distinct domains outside the HIRA WD repeat region. HIRIP3 (603365) interacted with HIRA and with H2B and H3 core histones (see 142711) in vitro, suggesting to Lorain et al. (1998) that a HIRA-HIRIP3-containing complex could function in some aspects of chromatin and histone metabolism.
In senescent cells, specialized domains of transcriptionally silent senescence-associated heterochromatic foci (SAHF), containing heterochromatin proteins such as HP1 (CBX5; 604478), are believed to repress expression of proliferation-promoting genes, which leads to senescence-associated cell cycle exit. Zhang et al. (2005) found that interaction between HIRA and ASF1A (609189) is rate limiting for the formation of SAHF. The 2 proteins appeared to interact within a pathway involving the flux of heterochromatic proteins through PML (102578) nuclear bodies.
Sesame (ssm) is a unique Drosophila maternal-effect mutant that prevents male pronucleus formation. Loppin et al. (2005) showed that ssm is a point mutation in the Hira gene, thus demonstrating that the histone chaperone protein HIRA is required for nucleosome assembly during sperm nucleus decondensation. Loppin et al. (2005) also showed that nucleosomes containing H3.3 (see H3.3A, 601128) and not H3, are specifically assembled in paternal Drosophila chromatin before the first round of DNA replication. The exclusive marking of paternal chromosomes with H3.3 represents a primary epigenetic distinction between parental genomes in the zygote, and underlines an important consequence of the critical and highly specialized function of HIRA at fertilization.
Hajkova et al. (2008) studied epigenetic changes in primordial germ cells (PGCs) in the mouse lineage. They showed that the chromatin changes occur in 2 steps. The first changes in nascent PGCs at embryonic day 8.5 establish a distinctive chromatin signature that is reminiscent of pluripotency. Next, when PGCs are residing in the gonads, major changes occur in nuclear architecture accompanied by an extensive erasure of several histone modifications and exchange of histone variants. Furthermore, the histone chaperones HIRA and NAP1 (164060), which are implicated in histone exchange, accumulate in PGC nuclei undergoing reprogramming. Hajkova et al. (2008) therefore suggested that the mechanism of histone replacement is critical for these chromatin rearrangements to occur. The marked chromatin changes are intimately linked with genomewide DNA demethylation. On the basis of the timing of the observed events, Hajkova et al. (2008) proposed that if DNA demethylation entails a DNA repair-based mechanism, the evident histone replacement would represent a repair-induced response event rather than being a prerequisite.
Banaszynski et al. (2013) found that deposition of H3.3 at promoters of developmentally regulated genes to establish a bivalent chromatin landscape in mouse embryonic stem cells (ESCs) was dependent on Hira. Hira colocalized with promoter-proximal RNA polymerase II (see 180660) and Polycomb repressive complex-2 (PRC2; see 301036) at promoters of developmentally regulated genes in ESCs, and Hira -/- ESCs recapitulated the loss of H3K27me3 and PRC2 at bivalent promoters observed in H3.3-depleted ESCs. Recruitment of PRC2 to promoters was H3.3 dependent, as Hira interacted with PRC2, and the interaction required H3.3.
Llevadot et al. (1996) reported that the TUPLE1 gene has 24 exons and spans about 60 kb on human chromosome 22. The introns vary in size from 0.4 to 8.7 kb with most being approximately 2 kb.
Halford et al. (1993) demonstrated that the TUPLE1 gene maps to chromosome 22 and to the shortest region of deletion overlap in a series of over 100 patients with the DiGeorge syndrome (DGS; 188400), velocardiofacial syndrome (VCFS; 192430), or a related disorder.
Mattei et al. (1994) mapped the mouse Tuple1 gene to chromosome 16 by isotopic in situ hybridization. The experiments were carried out using metaphase spreads from a WMP male mouse in which all of the autosomes, except 19, were in the form of metacentric Robertsonian translocations. In the human, TUPLE1 is centromeric to COMT (116790), which in turn is centromeric to IGLC1 (147220); all of these expressed sequences map to mouse chromosome 16.
Banaszynski, L. A., Wen, D., Dewell, S., Whitcomb, S. J., Lin, M., Diaz, N., Elsasser, S. J., Chapgier, A., Goldberg, A. D., Canaani, E., Rafii, S., Zheng, D., Allis, C. D. Hira-dependent histone H3.3 deposition facilitates PRC2 recruitment at developmental loci in ES cells. Cell 155: 107-120, 2013. [PubMed: 24074864] [Full Text: https://doi.org/10.1016/j.cell.2013.08.061]
Hajkova, P., Ancelin, K., Waldmann, T., Lacoste, N., Lange, U. C., Cesari, F., Lee, C., Almouzni, G., Schneider, R., Surani, M. A. Chromatin dynamics during epigenetic reprogramming in the mouse germ line. Nature 452: 877-881, 2008. [PubMed: 18354397] [Full Text: https://doi.org/10.1038/nature06714]
Halford, S., Wilson, D. I., Daw, S. C. M., Roberts, C., Wadey, R., Kamath, S., Wickremasinghe, A., Burn, J., Goodship, J., Mattei, M.-G., Moorman, A. F. M., Scambler, P. J. Isolation of a gene expressed during early embryogenesis from the region of 22q11 commonly deleted in DiGeorge syndrome.. Hum. Molec. Genet. 2: 1577-1582, 1993. [PubMed: 8268909] [Full Text: https://doi.org/10.1093/hmg/2.10.1577]
Lamour, V., Lecluse, Y., Desmaze, C., Spector, M., Bodescot, M., Aurias, A., Osley, M. A., Lipinski, M. A human homolog of the S. cerevisiae HIR1 and HIR2 transcriptional repressors cloned from the DiGeorge syndrome critical region. Hum. Molec. Genet. 4: 791-799, 1995. [PubMed: 7633437] [Full Text: https://doi.org/10.1093/hmg/4.5.791]
Llevadot, R., Scambler, P., Estivill, X., Pritchard, M. Genomic organization of TUPLE1/HIRA: a gene implicated in DiGeorge syndrome. Mammalian Genome 7: 911-914, 1996. [PubMed: 8995764] [Full Text: https://doi.org/10.1007/s003359900268]
Loppin, B., Bonnefoy, E., Anselme, C., Laurencon, A., Karr, T. L., Couble, P. The histone H3.3 chaperone HIRA is essential for chromatin assembly in the male pronucleus. Nature 437: 1386-1390, 2005. [PubMed: 16251970] [Full Text: https://doi.org/10.1038/nature04059]
Lorain, S., Quivy, J.-P., Monier-Gavelle, F., Scamps, C., Lecluse, Y., Almouzni, G., Lipinski, M. Core histones and HIRIP3, a novel histone-binding protein, directly interact with WD repeat protein HIRA. Molec. Cell. Biol. 18: 5546-5556, 1998. [PubMed: 9710638] [Full Text: https://doi.org/10.1128/MCB.18.9.5546]
Magnaghi, P., Roberts, C., Lorain, S., Lipinski, M., Scambler, P. J. HIRA, a mammalian homologue of Saccharomyces cerevisiae transcriptional co-repressors, interacts with Pax3. Nature Genet. 20: 74-77, 1998. [PubMed: 9731536] [Full Text: https://doi.org/10.1038/1739]
Mattei, M.-G., Halford, S., Scambler, P. J. Mapping of the Tuple1 gene to mouse chromosome 16A-B1. Genomics 23: 717-718, 1994. [PubMed: 7851908] [Full Text: https://doi.org/10.1006/geno.1994.1568]
Roberts, C., Daw, S. C. M., Halford, S., Scambler, P. J. Cloning and developmental expression analysis of chick Hira (Chira), a candidate gene for DiGeorge syndrome. Hum. Molec. Genet. 6: 237-245, 1997. [PubMed: 9063744] [Full Text: https://doi.org/10.1093/hmg/6.2.237]
Wilming, L. G., Snoeren, C. A. S., van Rijswijk, A., Grosveld, F., Meijers, C. The murine homologue of HIRA, a DiGeorge syndrome candidate gene, is expressed in embryonic structures affected in human CATCH22 patients. Hum. Molec. Genet. 6: 247-258, 1997. [PubMed: 9063745] [Full Text: https://doi.org/10.1093/hmg/6.2.247]
Zhang, R., Poustovoitov, M. V., Ye, X., Santos, H. A., Chen, W., Daganzo, S. M., Erzberger, J. P., Serebriiskii, I. G., Canutescu, A. A., Dunbrack, R. L., Pehrson, J. R., Berger, J. M., Kaufman, P. D., Adams, P. D. Formation of MacroH2A-containing senescense-associated heterochromatin foci and senescense driven by ASF1a and HIRA. Dev. Cell 8: 19-30, 2005. [PubMed: 15621527] [Full Text: https://doi.org/10.1016/j.devcel.2004.10.019]