title: CBFA2T3-ZNF652 corepressor complex regulates transcription of the E-box gene HEB.
abstract: Transcriptional repression plays a critical role in development and homeostasis. The ETO family represents a group of highly conserved and ubiquitously expressed transcriptional regulatory proteins that are components of a diverse range of multiprotein repressor complexes. ETO proteins function as transcriptional repressors by interacting with a number of transcription factors that bind to their cognate consensus DNA binding sequences within the promoters of target genes. We previously reported that the classical C(2)H(2) zinc finger DNA-binding protein, ZNF652, specifically and functionally interacts with the ETO protein CBFA2T3 and has a role in the suppression of breast oncogenesis. Here we report the identification and validation of the ZNF652 consensus DNA binding sequence. Our results show that the E-box gene HEB is a direct target of CBFA2T3-ZNF652-mediated transcriptional repression. The CBFA2T3-ZNF652 complex regulates HEB expression by binding to a single ZNF652 response element located within the promoter sequence of HEB. This study also shows that the NHR3 and NHR4 domains of CBFA2T3 interact with a conserved proline-rich region located within the C terminus of ZNF652. Our results, together with previous reports, indicate that HEB has a complex relationship with CBFA2T3; CBFA2T3 interacts with ZNF652 to repress HEB expression, and in addition CBFA2T3 interacts with the HEB protein to inhibit its activator function. These findings suggest that CBFA2T3-ZNF652-mediated HEB regulation may play an important role in hematopoiesis and myogenesis.
authors.affiliation: Breast Cancer Genetics Group, Dame Roma Mitchell Cancer Research Laboratories, Discipline of Medicine, University of Adelaide, Adelaide, South Australia 5000, Australia. ramam.sharma@imvs.sa.gov.au
authors.forename: Raman
authors.initials: R
authors.lastname: Kumar
authors.forename: Kelly M
authors.initials: KM
authors.lastname: Cheney
authors.forename: Ross
authors.initials: R
authors.lastname: McKirdy
authors.forename: Paul M
authors.initials: PM
authors.lastname: Neilsen
authors.forename: Renèe B
authors.initials: RB
authors.lastname: Schulz
authors.forename: Jaclyn
authors.initials: J
authors.lastname: Lee
authors.forename: Juliane
authors.initials: J
authors.lastname: Cohen
authors.forename: Grant W
authors.initials: GW
authors.lastname: Booker
authors.forename: David F
authors.initials: DF
authors.lastname: Callen
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000096:biosynthesis* / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism*; D016466:CHO Cells; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism*; D006224:Cricetinae; D003412:Cricetulus; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006801:Humans; D019169:Jurkat Cells; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism*; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D000075142:RUNX1 Translocation Partner 1 Protein; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D020218:Response Elements / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D004268:DNA-Binding Proteins; D046912:Multiprotein Complexes; D010750:Phosphoproteins; D011518:Proto-Oncogene Proteins; D000075142:RUNX1 Translocation Partner 1 Protein; D012097:Repressor Proteins; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C115744:CBFA2T3 protein, human; C082222:RUNX1T1 protein, human; C525993:ZNF652 protein, human; C073366:TCF12 protein, human