Bcl-xL is important for the antiapoptotic activity of Gfi1 and is upregulated by Gfi1 through hemgn.

Abstract

Gfi1 is a transcriptional repressor that plays a critical role in hematopoiesis. Gfi1 represses its target genes primarily through interacting with the histone demethylase LSD1 via its SNAG domain. A major function of Gfi1 is to inhibit DNA damage-induced apoptosis through its involvement in post-translational modifications and subsequent inhibition of p53 protein, and in PRMT1-dependent methylation of MRE11 and 53BP1, which is necessary for these proteins to function in DNA repair. We show here that Gfi1 inhibited apoptosis induced not only by DNA damage but also by growth factor withdrawal, inhibitory cytokine TGF-β and MYC activation. We further demonstrate that Gfi1 upregulated the expression of the pro-survival Bcl-2 family member Bcl-xL in a manner that was independent of p53. Bcl-xL overexpression partially rescued the hypersensitivity to DNA damage of Gfi1-knocked down leukemic cells and Gfi1-deficient mouse primary bone marrow (BM) cells. In contrast, Bcl-xL knockdown partially abolished the protective effect of Gfi1 on DNA damage-induced apoptosis. Notably, interaction with LSD1 was required and sufficient for Gfi1-mediaed upregulation of Bcl-xL, suggesting that Gfi1 may augment Bcl-xL expression by an indirect mechanism. We further demonstrate that Bcl-xL upregulation by Gfi1 was dependent on Hemgn upregulation, which results from Gfi1-mediated repression of PU.1. Our data reveal a novel mechanism by which Gfi1 inhibits apoptosis.