Epigenetic regulation of hematopoietic differentiation by Gfi-1 and Gfi-1b is mediated by the cofactors CoREST and LSD1.
Gfi-1 and Gfi-1b are homologous transcriptional repressors involved in diverse developmental contexts, including hematopoiesis and oncogenesis. Transcriptional repression by Gfi proteins requires the conserved SNAG domain. To elucidate the function of Gfi proteins, we purified Gfi-1b complexes and identified interacting proteins. Prominent among these is the corepressor CoREST, the histone demethylase LSD1, and HDACs 1 and 2. CoREST and LSD1 associate with Gfi-1/1b via the SNAG repression domain. Gfi-1b further recruits these cofactors to the majority of target gene promoters in vivo. Inhibition of CoREST and LSD1 perturbs differentiation of erythroid, megakaryocytic, and granulocytic cells as well as primary erythroid progenitors. LSD1 depletion derepresses Gfi targets in lineage-specific patterns, accompanied by enhanced histone 3 lysine 4 methylation at the respective promoters. Overall, we show that chromatin regulatory proteins CoREST and LSD1 mediate transcriptional repression by Gfi proteins. Lineage-restricted deployment of these cofactors through interaction with Gfi proteins controls hematopoietic differentiation.
Saleque
Shireen
S
Division of Hematology-Oncology, Children's Hospital Boston, Boston, Harvard Medical School, Boston, MA 02115, USA.
Kim
Jonghwan
J
Rooke
Heather M
HM
Orkin
Stuart H
SH
D000595:Amino Acid Sequence; D000818:Animals; D002454:Cell Differentiation / Q000235:genetics*; D045744:Cell Line, Tumor; D019070:Cell Lineage; D056970:Co-Repressor Proteins; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism*; D044127:Epigenesis, Genetic; D041905:Erythroid Cells / Q000166:cytology; D006410:Hematopoiesis / Q000235:genetics*; D006655:Histone Deacetylases / Q000378:metabolism; D056466:Histone Demethylases; D006657:Histones / Q000378:metabolism; D051379:Mice; D008957:Models, Genetic; D008969:Molecular Sequence Data; D046912:Multiprotein Complexes / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D010089:Oxidoreductases, N-Demethylating / Q000172:deficiency / Q000378:metabolism*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000737:chemistry / Q000378:metabolism*; D034622:RNA Interference; D012097:Repressor Proteins / Q000737:chemistry / Q000378:metabolism*; D014157:Transcription Factors / Q000737:chemistry / Q000378:metabolism*
D056970:Co-Repressor Proteins; D004268:DNA-Binding Proteins; C079873:Gfi1 protein, mouse; C486395:Gfi1b protein, mouse; D006657:Histones; D046912:Multiprotein Complexes; D009419:Nerve Tissue Proteins; D011518:Proto-Oncogene Proteins; C485650:Rcor2 protein, mouse; D012097:Repressor Proteins; D014157:Transcription Factors; D056466:Histone Demethylases; C504076:KDM1a protein, mouse; D010089:Oxidoreductases, N-Demethylating; D006655:Histone Deacetylases