SUMOylation Regulates Growth Factor Independence 1 in Transcriptional Control and Hematopoiesis

Abstract

Cell fate specification requires precise coordination of transcription factors and their regulators to achieve fidelity and flexibility in lineage allocation. The transcriptional repressor growth factor independence 1 (GFI1) is comprised of conserved Snail/Slug/ Gfi1 (SNAG) and zinc finger motifs separated by a linker region poorly conserved with GFI1B, its closest homolog. Moreover, GFI1 and GFI1B coordinate distinct developmental fates in hematopoiesis, suggesting that their functional differences may derive from structures within their linkers. We show a binding interface between the GFI1 linker and the SP-RING domain of PIAS3, an E3-SUMO (small ubiquitin-related modifier) ligase. The PIAS3 binding region in GFI1 contains a conserved type I SUMOylation consensus element, centered on lysine-239 (K239). In silico prediction algorithms identify K239 as the only highprobability site for SUMO modification. We show that GFI1 is modified by SUMO at K239. SUMOylation-resistant derivatives of GFI1 fail to complement Gfi1 depletion phenotypes in zebrafish primitive erythropoiesis and granulocytic differentiation in cultured human cells. LSD1/CoREST recruitment and MYC repression by GFI1 are profoundly impaired for SUMOylation-resistant GFI1 derivatives, while enforced expression of MYC blocks granulocytic differentiation. These findings suggest that SUMOylation within the GFI1 linker favors LSD1/CoREST recruitment and MYC repression to govern hematopoietic differentiation.

Regulation of transcription factors by sumoylation

“…Recent studies continue to support HDAC recruitment as a major effect of TF SUMO modification. For example, a sumoylation-deficient form of GFI1, a repressor of haematopoietic stem cell genes, fails to associate efficiently with components of the CoREST HDAC and is defective in transcriptional repression, 18 while a form of glucocorticoid receptor (GR) that cannot be sumoylated is unable to recruit the NCoR1/SMRT HDAC to a subset of GR-repressed target genes. 19 HDACs are the most commonly implicated, but recruitment of other types of corepressors is also promoted by TF sumoylation.…”

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

“…Sequence-specific DNA binding by both GFI1 and GFI1B is coordinated by ZnFs 3, 4, and 5 (32,(35)(36)(37), while ZnFs 1, 2, and 6 enable protein-protein interactions with an incompletely defined subset of transcriptional partners (38)(39)(40)(41). Linker regions provide a platform for protein binding and posttranslational modifications that regulate innate functions of GFI proteins (40,42). GFI1 and GFI1B SNAG domains differ only by a conservative S¡T substitution at amino acid 14; they are otherwise identical.…”

Bortezomib‐induced peripheral neuropathy: A genome‐wide association study on multiple myeloma patients

“…The rs6552496 is located within a binding site for Foxo, Gfi, and Gfi1b that function as transcriptional repressors. These proteins play a role in diverse developmental contexts, including neutrophil differentiation, hematopoiesis, and oncogenesis …”

“…These proteins play a role in diverse developmental contexts, including neutrophil differentiation, hematopoiesis, and oncogenesis. 23,24 The rs12521286 and other highly linked SNPs affect gene expression of the neighboring genes CTD-2201I18.1 and THBS4 in esophagus The rs17748074 resides within an intronic region of DCC (deleted in colorectal cancer). It was originally found to be a prognostic tumor marker and subsequently identified as a receptor for netrin-1.…”