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Gene Review

HIRA  -  histone cell cycle regulator

Homo sapiens

Synonyms: DGCR1, HIR, Protein HIRA, TUP1, TUP1-like enhancer of split protein 1, ...
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Disease relevance of HIRA

  • HIRA homologs are expressed in a regulated fashion during mouse and chicken embryogenesis, and the human gene is a major candidate for the DiGeorge syndrome and related developmental disorders caused by a reduction to single dose of a fragment of chromosome 22q [1].
  • In this report we describe the use of the baculovirus expression system to overproduce the human insulin holoreceptor (HIR) and a truncated, secretory version of the HIR cDNA (HIRsec) consisting of the alpha subunit and the extracellular portion of the beta subunit (beta') [2].
  • To clarify this issue, we characterized HIR and IGF-1R in placenta at term from normal women, normoinsulinaemic women with gestational hypertension (NGH), and hyperinsulinaemic women with gestational hypertension (HGH) [3].
  • Expression of mRNA and protein for PLD1 and PLD2 was analyzed in the following cell lines: A7r5 (rat vascular smooth muscle); EL4 (mouse thymoma); HL-60 (human myeloid leukemia); Jurkat (human leukemia); PC-3 (human prostate adenocarcinoma); PC-12K (rat phaeochromocytoma); and Rat-1 HIR (rat fibroblast) [4].
  • METHODS: Eighty-four children with sporadic tetralogy of Fallot (40 boys and 44 girls; mean age, 34 months) were analyzed for microdeletion at chromosome 22q11 by genotype analysis, using five microsatellite markers, D22S427, D22S941, D22S944, D22S264 and D22S311, and confirmed by quantitative polymerase chain reaction, using TUPLE1 and D22S264 [5].

High impact information on HIRA

  • Thus, altered stoichiometry of complexes containing HIRA may be important for the development of structures affected in WS and DGS [6].
  • Applying MobyDick to the genes derepressed when the general repressor Tup1 is deleted, we find known as well as putative binding sites for its regulatory partners [7].
  • Insulin also induced the expression of the protooncogene c-fos and the early growth response gene Egr-1 in HIR delta 978 cells far greater than in parental Rat1 fibroblasts [8].
  • Although these truncated IRs were inactive with respect to ligand-induced internalization and autophosphorylation, insulin stimulated endogenous substrate (pp185) phosphorylation significantly more in HIR delta 978 cells than in untransfected Rat1 cells [8].
  • Dex decreased basal glucose metabolic clearance to the same extent in LIR and HIR [9].

Biological context of HIRA


Anatomical context of HIRA

  • Orthologues of the DGS candidate gene HIRA are expressed in the neural crest and in neural crest-derived tissues in both chick and mouse embryos [13].
  • Using both biochemical and immunofluorescence techniques, a minor fraction of HIRA was found tightly associated with the nuclear matrix, the material that remains after nuclease treatment and high-salt extraction [14].
  • The number of dermal fibroblasts containing damaged telomeres reaches a value of over 15% of total fibroblasts, whereas 80% of cells contain high levels of the heterochromatin protein HIRA [15].
  • Stable transfection of these cells with cDNA for the human insulin receptor yielded a cell line (3T3/HIR) expressing greater than 6 x 10(6) receptors/cell that was highly sensitive and responsive to insulin for stimulation of deoxy[14C]glucose uptake and [3H]thymidine incorporation [16].
  • When CHO cells transfected with del82 (CHO-del82) were stimulated with insulin, autophosphorylation was decreased to a great extent compared with cells expressing HIR (CHO-HIR) [17].

Associations of HIRA with chemical compounds

  • Hyperglycemic clamp revealed that Dex induced a significant increase (P less than 0.05) in insulin response only in HIR [9].
  • Importantly, despite absence of the beta-subunit cytoplasmic domain, fibroblasts expressing HIR delta 978 receptors displayed enhanced sensitivity to insulin for stimulation of glucose incorporation into glycogen, alpha-aminoisobutyric acid uptake, thymidine incorporation, and S6 kinase activity compared with parental fibroblasts [8].
  • Despite the ability to bind insulin and activate as a tyrosine kinase, HIR delta ex16 receptors do not internalize in Rat 1 cells [18].
  • However, expression of HIR delta CT receptors (Ro = 2.5 X 10(5] led to little, if any, increase in insulin sensitivity of either 2-deoxy-D-glucose uptake or glycogen synthase activation [19].
  • Transfection of chimeric chloramphenicol acetyltransferase plasmids containing various deletions and insertions of the promoter of HIR gene into CHO and COS cells indicated that the region between -629 and -1 (initiator ATG is +1) is sufficient for maximal promoter activity [20].

Other interactions of HIRA

  • The presence of a single copy of the HIRA gene in DGS patients possibly accounts for some of the abnormalities associated with this syndrome [21].
  • HIRIP3 (HIRA-interacting protein 3) is a novel gene product that was identified from its HIRA-binding properties in the yeast protein interaction trap [1].
  • We developed single-copy probes for three chromosomal regions-the CDC2L1 (chromosome 1p36), MAGEL2 (chromosome 15q11.2), and HIRA (chromosome 22q11.2) genes-and show their utility for FISH [22].
  • We describe here a new gene called NLVCF, which maps to the critical region for VCFS on 22q11 between the genes HIRA and UFD1L [23].
  • The LXXLL motif at positions 993-997 of HIRA is necessary for the in vitro interaction with HDAC-2 [24].

Analytical, diagnostic and therapeutic context of HIRA

  • Western blot analysis and double-immunofluorescence experiments using a specific antiserum revealed a primary nuclear localization of HIRA [1].
  • We report the crystal structure of an ASF1a-HIRA heterodimer and a biochemical dissection of ASF1a's mutually exclusive interactions with HIRA and the p60 subunit of CAF-1 [11].
  • Here, by using the gene targeting technique, we generated the homozygous HIRA-deficient DT40 mutant DeltaHIRA [25].
  • By using a cosmid probe (M51) and fluorescence in situ hybridization, we show here that the anonymous DNA marker locus D22S183 is within the SRO, between TUPLE1 and D22S75 (probe N25) [26].
  • The microdeletions were confirmed using quantitative PCR with markers TUPLE1, exon 2 of the UFD1L gene, and D22S264; the boundaries of these microdeletions were estimated using genotypic analyses of the unaffected family members [27].


  1. Core histones and HIRIP3, a novel histone-binding protein, directly interact with WD repeat protein HIRA. Lorain, S., Quivy, J.P., Monier-Gavelle, F., Scamps, C., Lécluse, Y., Almouzni, G., Lipinski, M. Mol. Cell. Biol. (1998) [Pubmed]
  2. Baculovirus-directed expression of the human insulin receptor and an insulin-binding ectodomain. Paul, J.I., Tavaré, J., Denton, R.M., Steiner, D.F. J. Biol. Chem. (1990) [Pubmed]
  3. Increased expression of low-affinity insulin receptor isoform and insulin/insulin-like growth factor-I hybrid receptors in term placenta from insulin-resistant women with gestational hypertension. Valensise, H., Liu, Y.Y., Federici, M., Lauro, D., Dell'anna, D., Romanini, C., Sesti, G. Diabetologia (1996) [Pubmed]
  4. Expression and regulation of phospholipase D isoforms in mammalian cell lines. Gibbs, T.C., Meier, K.E. J. Cell. Physiol. (2000) [Pubmed]
  5. Prevalence and parental origin in Tetralogy of Fallot associated with chromosome 22q11 microdeletion. Lu, J.H., Chung, M.Y., Hwang, B., Chien, H.P. Pediatrics (1999) [Pubmed]
  6. HIRA, a mammalian homologue of Saccharomyces cerevisiae transcriptional co-repressors, interacts with Pax3. Magnaghi, P., Roberts, C., Lorain, S., Lipinski, M., Scambler, P.J. Nat. Genet. (1998) [Pubmed]
  7. Building a dictionary for genomes: identification of presumptive regulatory sites by statistical analysis. Bussemaker, H.J., Li, H., Siggia, E.D. Proc. Natl. Acad. Sci. U.S.A. (2000) [Pubmed]
  8. Transmembrane signaling by an insulin receptor lacking a cytoplasmic beta-subunit domain. Sasaoka, T., Takata, Y., Kusari, J., Anderson, C.M., Langlois, W.J., Olefsky, J.M. Proc. Natl. Acad. Sci. U.S.A. (1993) [Pubmed]
  9. The diabetogenic effects of glucocorticoids are more pronounced in low- than in high-insulin responders. Wajngot, A., Giacca, A., Grill, V., Vranic, M., Efendic, S. Proc. Natl. Acad. Sci. U.S.A. (1992) [Pubmed]
  10. Structural Organization of the WD repeat protein-encoding gene HIRA in the DiGeorge syndrome critical region of human chromosome 22. Lorain, S., Demczuk, S., Lamour, V., Toth, S., Aurias, A., Roe, B.A., Lipinski, M. Genome Res. (1996) [Pubmed]
  11. Structure of a human ASF1a-HIRA complex and insights into specificity of histone chaperone complex assembly. Tang, Y., Poustovoitov, M.V., Zhao, K., Garfinkel, M., Canutescu, A., Dunbrack, R., Adams, P.D., Marmorstein, R. Nat. Struct. Mol. Biol. (2006) [Pubmed]
  12. HIRA, the human homologue of yeast Hir1p and Hir2p, is a novel cyclin-cdk2 substrate whose expression blocks S-phase progression. Hall, C., Nelson, D.M., Ye, X., Baker, K., DeCaprio, J.A., Seeholzer, S., Lipinski, M., Adams, P.D. Mol. Cell. Biol. (2001) [Pubmed]
  13. HIRA, a DiGeorge syndrome candidate gene, is required for cardiac outflow tract septation. Farrell, M.J., Stadt, H., Wallis, K.T., Scambler, P., Hixon, R.L., Wolfe, R., Leatherbury, L., Kirby, M.L. Circ. Res. (1999) [Pubmed]
  14. Subnuclear localization and mitotic phosphorylation of HIRA, the human homologue of Saccharomyces cerevisiae transcriptional regulators Hir1p/Hir2p. De Lucia, F., Lorain, S., Scamps, C., Galisson, F., MacHold, J., Lipinski, M. Biochem. J. (2001) [Pubmed]
  15. Accumulation of senescent cells in mitotic tissue of aging primates. Jeyapalan, J.C., Ferreira, M., Sedivy, J.M., Herbig, U. Mech. Ageing Dev. (2007) [Pubmed]
  16. The metabolic and mitogenic effects of both insulin and insulin-like growth factor are enhanced by transfection of insulin receptors into NIH3T3 fibroblasts. Hofmann, C., Goldfine, I.D., Whittaker, J. J. Biol. Chem. (1989) [Pubmed]
  17. Normal insulin receptor substrate-1 phosphorylation in autophosphorylation-defective truncated insulin receptor. Evidence that phosphorylation of substrates might be sufficient for certain biological effects evoked by insulin. Yamamoto-Honda, R., Kadowaki, T., Momomura, K., Tobe, K., Tamori, Y., Shibasaki, Y., Mori, Y., Kaburagi, Y., Koshio, O., Akanuma, Y. J. Biol. Chem. (1993) [Pubmed]
  18. A domain of the insulin receptor required for endocytosis in rat fibroblasts. Thies, R.S., Webster, N.J., McClain, D.A. J. Biol. Chem. (1990) [Pubmed]
  19. Properties of a human insulin receptor with a COOH-terminal truncation. II. Truncated receptors have normal kinase activity but are defective in signaling metabolic effects. Maegawa, H., McClain, D.A., Freidenberg, G., Olefsky, J.M., Napier, M., Lipari, T., Dull, T.J., Lee, J., Ullrich, A. J. Biol. Chem. (1988) [Pubmed]
  20. A cluster of four Sp1 binding sites required for efficient expression of the human insulin receptor gene. Araki, E., Murakami, T., Shirotani, T., Kanai, F., Shinohara, Y., Shimada, F., Mori, M., Shichiri, M., Ebina, Y. J. Biol. Chem. (1991) [Pubmed]
  21. A human homolog of the S. cerevisiae HIR1 and HIR2 transcriptional repressors cloned from the DiGeorge syndrome critical region. Lamour, V., Lécluse, Y., Desmaze, C., Spector, M., Bodescot, M., Aurias, A., Osley, M.A., Lipinski, M. Hum. Mol. Genet. (1995) [Pubmed]
  22. Sequence-based design of single-copy genomic DNA probes for fluorescence in situ hybridization. Rogan, P.K., Cazcarro, P.M., Knoll, J.H. Genome Res. (2001) [Pubmed]
  23. Isolation and characterization of a human gene containing a nuclear localization signal from the critical region for velo-cardio-facial syndrome on 22q11. Funke, B., Puech, A., Saint-Jore, B., Pandita, R., Skoultchi, A., Morrow, B. Genomics (1998) [Pubmed]
  24. WD dipeptide motifs and LXXLL motif of chicken HIRA are necessary for transcription repression and the latter motif is essential for interaction with histone deacetylase-2 in vivo. Ahmad, A., Takami, Y., Nakayama, T. Biochem. Biophys. Res. Commun. (2003) [Pubmed]
  25. 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. Ahmad, A., Kikuchi, H., Takami, Y., Nakayama, T. J. Biol. Chem. (2005) [Pubmed]
  26. Positional mapping of loci in the DiGeorge critical region at chromosome 22q11 using a new marker (D22S183). Mulder, M.P., Wilke, M., Langeveld, A., Wilming, L.G., Hagemeijer, A., van Drunen, E., Zwarthoff, E.C., Riegman, P.H., Deelen, W.H., van den Ouweland, A.M. Hum. Genet. (1995) [Pubmed]
  27. Molecular characterization of tetralogy of fallot within Digeorge critical region of the chromosome 22. Lu, J.H., Chung, M.Y., Betau, H., Chien, H.P., Lu, J.K. Pediatric cardiology. (2001) [Pubmed]
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