Growth Factor Independence 1B-Mediated Transcriptional Repression and Lineage Allocation Require Lysine-Specific Demethylase 1-Dependent Recruitment of the BHC Complex

Abstract

Growth factor independence 1B (GFI1B) coordinates assembly of transcriptional repressor complexes comprised of corepressors 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 GFI1B’s obligate effector, lysine-specific demethylase 1 (LSD1). 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 acquisition of erythroid traits by K562 cells. Among these elements, depletion of both HMG20A and HMG20B or of GSE1 blocks 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.

Pharmacological inhibition of LSD1 triggers myeloid differentiation by targeting GSE1, a novel oncogene in AML

“…3A, Table S1). This is in line with the evidence that GSE1 is mainly associated with co-repressor complexes, such as the HDAC2 and BHC complexes 35,37 . Intersecting the differentially expressed genes (DEG) in common between the two KD conditions, we obtained 422 common up-regulated and 47 common down-regulated genes (Fig.…”

“…It is made available under a preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in The copyright holder for this this version posted February 16, 2021. ; https://doi.org/10.1101/2021.02.16.431315 doi: bioRxiv preprint 5 GSE1 in neuro-epithelial stem (NES) cells 33 . GSE1 effect in haematological malignancies and AML in particular has not been investigated yet, especially in the context of its physical and functional interaction with LSD1 [34][35][36][37] .…”

Targeting the GFI1/1B—CoREST Complex in Acute Myeloid Leukemia

“…Finally, we and others showed that many proteins associate with CoREST in the context of GFI1/1B (32, 35, 57). Although the effect on CoREST function has been studied for some of these factors, the role of others like ZNF217, and PHF21A is still unclear.…”

Multifaceted Actions of GFI1 and GFI1B in Hematopoietic Stem Cell Self-Renewal and Lineage Commitment

“…At the N-terminus of the proteins, there is a highly conserved SNAIL/ GFI1 (SNAG) domain that is present in both GFI1 and GFI1B with ~90% homology, forming a sub-family on their own. This domain is shared with other transcriptional repressors such as SNAIL, SCRATCH, and SLUG forming a distinct but larger SNAG protein sub-family (Grimes et al, 1996;Manzanares et al, 2001;Katoh andKatoh, 2003, andreviewed in Chiang andAyyanathan, 2013) and mediates transcriptional repression by recruiting chromatin modifier complexes to the regulatory regions of GFI1/GFI1B target genes (Tong et al, 1998;Saleque et al, 2007;Velinder et al, 2016;McClellan et al, 2019).…”