HIRA, A MAMMALIAN HOMOLOG OF SACCHAROMYCES-CEREVISIAE TRANSCRIPTIONALCO-REPRESSORS, INTERACTS WITH PAX3

HIRA maps to the DiGeorge/velocardiofacial syndrome critical region (D GCR) at 22q11 (refs 1,2) and encodes a WD40 repeat protein similar to yeast Hir1p and Hir2p. These transcriptional co-repressors regulate ce ll cycle-dependent histone gene transcription(3), possibly by remodell ing local chromatin structure. We report an interaction between HIRA a nd the transcription factor Pax3. Pax3 haploinsufficiency results in t he mouse splotch and human Waardenburg syndrome (WSI and WSIII) phenot ypes. Mice homozygous for Pax3 mutations die in utero with a phenocopy of DCS, or neonatally with neural tube defects. HIRA was also found t o interact with core histones. Thus, altered stoichiometry of complexe s containing HIRA may be important for the development of structures a ffected in WS and DCS.