Growth Factor Independence (GFI) 1B-mediated transcriptional repression and lineage allocation require Lysine Specific Demethylase (LSD)1-dependent recruitment of the BHC complex

Abstract

Growth Factor Independence (GFI)1B coordinates assembly of transcriptional repressor complexes comprised of co-repressors and histone modifying enzymes to control gene expression programs governing lineage allocation in hematopoiesis. Enforced expression of GFI1B in K562 erythroleukemia cells favors erythroid over megakaryocytic differentiation, providing a platform to define molecular determinants of binary fate decisions triggered by GFI1B. We deployed proteome-wide proximity labeling to identify factors whose inclusion in GFI1B complexes depends upon GFI1Bs obligate effector, Lysine Specific Demethylase (LSD)1. We show that GFI1B preferentially recruits core and putative elements of the BRAF-histone deacetylase (HDAC) (BHC) chromatin remodeling complex (LSD1, RCOR1, HMG20A, HMG20B, HDAC1, HDAC2, PHF21A, GSE1, ZMYM2 and ZNF217) in an LSD1-dependent manner to control erythroid fate specification. Among these, depletion of both HMG20A and HMG20B, or GSE1 block GFI1B-mediated erythroid differentiation, phenocopying impaired differentiation brought on by LSD1 depletion or disruption of GFI1B--LSD1 binding. These findings demonstrate the central role of the GFI1B--LSD1 interaction as a determinant of BHC complex recruitment to enable cell fate decisions driven by GFI1B.