Work

Transcription factor LSF-DNMT1 complex dissociation by FQI1 leads to aberrant DNA methylation and gene expression

Year: 2016

Type: article

Abstract: // Hang Gyeong Chin 1, 2 , V.K. Chaithanya Ponnaluri 1 , Guoqiang Zhang 1 , Pierre-Olivier Estève 1 , Scott E. Schaus 3 , Ulla Hansen 2, 4 , Sriharsa Pradhan 1 1 New England Biolabs, Inc. Ipswich, MA 01938, USA 2 MCBB Graduate Program, Boston University, Boston, MA 02215, USA 3 Deptartment of Chemistry, Center for Molecular Discovery, Boston University, Boston, MA 02215, USA 4 Department of Biology, Boston University, Boston, MA 02215, USA Correspondence to: Ulla Hansen, email: [email protected] Sriharsa Pradhan, email: [email protected] Keywords: DNA methylation, transcription factor LSF, gene expression, HCC Received: August 04, 2016 Accepted: October 13, 2016 Published: November 10, 2016 ABSTRACT The transcription factor LSF is highly expressed in hepatocellular carcinoma (HCC) and promotes oncogenesis. Factor quinolinone inhibitor 1 (FQI1), inhibits LSF DNA-binding activity and exerts anti-proliferative activity. Here, we show that LSF binds directly to the maintenance DNA (cytosine-5) methyltransferase 1 (DNMT1) and its accessory protein UHRF1 both in vivo and in vitro . Binding of LSF to DNMT1 stimulated DNMT1 activity and FQI1 negated the methyltransferase activation. Addition of FQI1 to the cell culture disrupted LSF bound DNMT1 and UHRF1 complexes, resulting in global aberrant CpG methylation. Differentially methylated regions (DMR) containing at least 3 CpGs, were significantly altered by FQI1 compared to control cells. The DMRs were mostly concentrated in CpG islands, proximal to transcription start sites, and in introns and known genes. These DMRs represented both hypo and hypermethylation, correlating with altered gene expression. FQI1 treatment elicits a cascade of effects promoting altered cell cycle progression. These findings demonstrate a novel mechanism of FQI1 mediated alteration of the epigenome by DNMT1-LSF complex disruption, leading to aberrant DNA methylation and gene expression.

Source: Oncotarget

DOI: 10.18632/oncotarget.13271