HIRA

Histone cell cycle regulator
PDB rendering based on 2i32.
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 2I32​
Identifiers
Symbols	HIRA ; DGCR1; TUP1; TUPLE1
External IDs	OMIM: 600237 MGI: 99430 HomoloGene: 48172 GeneCards: HIRA Gene
Gene ontology Molecular function • transcription factor activity, sequence-specific DNA binding • transcription corepressor activity • protein binding Cellular component • nuclear chromatin • nucleus • nucleoplasm • PML body • protein complex • extracellular exosome Biological process • osteoblast differentiation • DNA replication-independent nucleosome assembly • transcription, DNA-templated • regulation of transcription from RNA polymerase II promoter • gastrulation • anatomical structure morphogenesis • chromatin modification • muscle cell differentiation • negative regulation of nucleic acid-templated transcription Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	7290	15260
Ensembl	ENSG00000100084	ENSMUSG00000022702
UniProt	P54198	Q61666
RefSeq (mRNA)	NM_003325	NM_001005228
RefSeq (protein)	NP_003316	NP_034565
Location (UCSC)	Chr 22: 19.33 – 19.45 Mb	Chr 16: 18.88 – 18.97 Mb
PubMed search

Protein HIRA is a protein that in humans is encoded by the HIRA gene.^[1][2][3][4] This gene is mapped to 22q11.21, centromeric to COMT.^[4]

Function

The specific function of this protein has yet to be determined; however, it has been speculated to play a role in transcriptional regulation and/or chromatin and histone metabolism.^[4]

Research done by Salomé Adam, Sophie E. Polo, and Geneviève Almouzni indicate that HIRA proteins are involved in restarting transcription after UVC damage^[5]

Clinical significance

It is considered the primary candidate gene in some haploinsufficiency syndromes such as DiGeorge syndrome, and insufficient production of the gene may disrupt normal embryonic development.^[4]

Model organisms

Hira knockout mouse phenotype

Characteristic	Phenotype
Homozygote viability	Abnormal
Fertility	Normal
Body weight	Normal
Anxiety	Normal
Neurological assessment	Normal
Grip strength	Normal
Hot plate	Normal
Dysmorphology	Normal
Indirect calorimetry	Normal
Glucose tolerance test	Normal
Auditory brainstem response	Normal
DEXA	Normal
Radiography	Normal
Body temperature	Normal
Eye morphology	Normal
Clinical chemistry	Normal
Haematology	Abnormal[6]
Peripheral blood lymphocytes	Normal
Micronucleus test	Normal
Heart weight	Normal
Eye Histopathology	Normal
Salmonella infection	Normal[7]
All tests and analysis from[8][9]

Model organisms have been used in the study of HIRA function. A conditional knockout mouse line, called Hira^{tm1a(EUCOMM)Wtsi[10][11]} was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists.^[12][13][14]

Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.^[8][15] Twenty two tests were carried out on mutant mice and two significant abnormalities were observed.^[8] No homozygous mutant mice survived until weaning. The remaining tests were carried out on heterozygous mutant adult mice and a decreased leukocyte cell number was recorded in male animals.^[8]

Interactions

HIRA has been shown to interact with HIST1H2BK.^[16]

References

1. Halford S, Wadey R, Roberts C, Daw SC, Whiting JA, O'Donnell H, Dunham I, Bentley D, Lindsay E, Baldini A (Mar 1994). "Isolation of a putative transcriptional regulator from the region of 22q11 deleted in DiGeorge syndrome, Shprintzen syndrome and familial congenital heart disease". Hum Mol Genet 2 (12): 2099–107. doi:10.1093/hmg/2.12.2099. PMID 8111380.
2. Lamour V, Lécluse Y, Desmaze C, Spector M, Bodescot M, Aurias A, Osley MA, Lipinski M (Sep 1995). "A human homolog of the S. cerevisiae HIR1 and HIR2 transcriptional repressors cloned from the DiGeorge syndrome critical region". Hum Mol Genet 4 (5): 791–9. doi:10.1093/hmg/4.5.791. PMID 7633437.
3. Magnaghi P, Roberts C, Lorain S, Lipinski M, Scambler PJ (Oct 1998). "HIRA, a mammalian homologue of Saccharomyces cerevisiae transcriptional co-repressors, interacts with Pax3". Nat Genet 20 (1): 74–7. doi:10.1038/1739. PMID 9731536.
4. "Entrez Gene: HIRA HIR histone cell cycle regulation defective homolog A (S. cerevisiae)".
5. Adam, S., Polo, S. E., & Almouzni, G. (2013). Transcription Recovery after DNA Damage Requires Chromatin Priming by the H3.3 Histone Chaperone HIRA. Cell, 155(1), 94-106. Retrieved from http://www.cell.com/abstract/S0092-8674(13)01023-4
6. "Haematology data for Hira". Wellcome Trust Sanger Institute.
7. "Salmonella infection data for Hira". Wellcome Trust Sanger Institute.
8. Gerdin AK (2010). "The Sanger Mouse Genetics Programme: High throughput characterisation of knockout mice". Acta Ophthalmologica 88: 925–7. doi:10.1111/j.1755-3768.2010.4142.x.
9. Mouse Resources Portal, Wellcome Trust Sanger Institute.
10. "International Knockout Mouse Consortium".
11. "Mouse Genome Informatics".
12. Skarnes WC, Rosen B, West AP, Koutsourakis M, Bushell W, Iyer V, Mujica AO, Thomas M, Harrow J, Cox T, Jackson D, Severin J, Biggs P, Fu J, Nefedov M, de Jong PJ, Stewart AF, Bradley A (2011). "A conditional knockout resource for the genome-wide study of mouse gene function". Nature 474 (7351): 337–342. doi:10.1038/nature10163. PMC 3572410. PMID 21677750.
13. Dolgin E (2011). "Mouse library set to be knockout". Nature 474 (7351): 262–3. doi:10.1038/474262a. PMID 21677718.
14. Collins FS, Rossant J, Wurst W (2007). "A Mouse for All Reasons". Cell 128 (1): 9–13. doi:10.1016/j.cell.2006.12.018. PMID 17218247.
15. van der Weyden L, White JK, Adams DJ, Logan DW (2011). "The mouse genetics toolkit: revealing function and mechanism.". Genome Biol 12 (6): 224. doi:10.1186/gb-2011-12-6-224. PMC 3218837. PMID 21722353.
16. Lorain S, Quivy JP, Monier-Gavelle F, Scamps C, Lécluse Y, Almouzni G, Lipinski M (September 1998). "Core histones and HIRIP3, a novel histone-binding protein, directly interact with WD repeat protein HIRA". Mol. Cell. Biol. 18 (9): 5546–56. PMC 109139. PMID 9710638.

Further reading

• Lorain S, Demczuk S, Lamour V, Toth S, Aurias A, Roe BA, Lipinski M (1996). "Structural Organization of the WD repeat protein-encoding gene HIRA in the DiGeorge syndrome critical region of human chromosome 22.". Genome Res. 6 (1): 43–50. doi:10.1101/gr.6.1.43. PMID 8681138.
• Llevadot R, Scambler P, Estivill X, Pritchard M (1997). "Genomic organization of TUPLE1/HIRA: a gene implicated in DiGeorge syndrome.". Mamm. Genome 7 (12): 911–4. doi:10.1007/s003359900268. PMID 8995764.
• Lorain S, Quivy JP, Monier-Gavelle F, Scamps C, Lécluse Y, Almouzni G, Lipinski M (1998). "Core histones and HIRIP3, a novel histone-binding protein, directly interact with WD repeat protein HIRA.". Mol. Cell. Biol. 18 (9): 5546–56. PMC 109139. PMID 9710638.
• Hall C, Nelson DM, Ye X, Baker K, DeCaprio JA, Seeholzer S, Lipinski M, Adams PD (2001). "HIRA, the human homologue of yeast Hir1p and Hir2p, is a novel cyclin-cdk2 substrate whose expression blocks S-phase progression.". Mol. Cell. Biol. 21 (5): 1854–65. doi:10.1128/MCB.21.5.1854-1865.2001. PMC 86753. PMID 11238922.
• Lorain S, Lécluse Y, Scamps C, Mattéi MG, Lipinski M (2001). "Identification of human and mouse HIRA-interacting protein-5 (HIRIP5), two mammalian representatives in a family of phylogenetically conserved proteins with a role in the biogenesis of Fe/S proteins.". Biochim. Biophys. Acta 1517 (3): 376–83. doi:10.1016/S0167-4781(00)00300-6. PMID 11342215.
• Lehner B, Sanderson CM (2004). "A protein interaction framework for human mRNA degradation.". Genome Res. 14 (7): 1315–23. doi:10.1101/gr.2122004. PMC 442147. PMID 15231747.
• Collins JE, Wright CL, Edwards CA, Davis MP, Grinham JA, Cole CG, Goward ME, Aguado B, Mallya M, Mokrab Y, Huckle EJ, Beare DM, Dunham I (2005). "A genome annotation-driven approach to cloning the human ORFeome.". Genome Biol. 5 (10): R84. doi:10.1186/gb-2004-5-10-r84. PMC 545604. PMID 15461802.
• Gocke CB, Yu H, Kang J (2005). "Systematic identification and analysis of mammalian small ubiquitin-like modifier substrates.". J. Biol. Chem. 280 (6): 5004–12. doi:10.1074/jbc.M411718200. PMID 15561718.
• Zhang R, Poustovoitov MV, Ye X, Santos HA, Chen W, Daganzo SM, Erzberger JP, Serebriiskii IG, Canutescu AA, Dunbrack RL, Pehrson JR, Berger JM, Kaufman PD, Adams PD (2005). "Formation of MacroH2A-containing senescence-associated heterochromatin foci and senescence driven by ASF1a and HIRA.". Dev. Cell 8 (1): 19–30. doi:10.1016/j.devcel.2004.10.019. PMID 15621527.
• Ahmad A, Kikuchi H, Takami Y, Nakayama T (2005). "Different roles of N-terminal and C-terminal halves of HIRA in transcription regulation of cell cycle-related genes that contribute to control of vertebrate cell growth.". J. Biol. Chem. 280 (37): 32090–100. doi:10.1074/jbc.M501426200. PMID 16024922.
• Tang Y, Poustovoitov MV, Zhao K, Garfinkel M, Canutescu A, Dunbrack R, Adams PD, Marmorstein R (2006). "Structure of a human ASF1a-HIRA complex and insights into specificity of histone chaperone complex assembly.". Nat. Struct. Mol. Biol. 13 (10): 921–9. doi:10.1038/nsmb1147. PMC 2933817. PMID 16980972.
• Zhang R, Chen W, Adams PD (2007). "Molecular dissection of formation of senescence-associated heterochromatin foci.". Mol. Cell. Biol. 27 (6): 2343–58. doi:10.1128/MCB.02019-06. PMC 1820509. PMID 17242207.