Oncotarget

Research Papers:

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

Hang Gyeong Chin, V.k. Chaithanya Ponnaluri, Guoqiang Zhang, Pierre-Olivier Estève, Scott E. Schaus, Ulla Hansen and Sriharsa Pradhan _

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Oncotarget. 2016; 7:83627-83640. https://doi.org/10.18632/oncotarget.13271

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Abstract

Hang Gyeong Chin1,2, V.K. Chaithanya Ponnaluri1, Guoqiang Zhang1, Pierre-Olivier Estève1, Scott E. Schaus3, Ulla Hansen2,4, Sriharsa Pradhan1

1New England Biolabs, Inc. Ipswich, MA 01938, USA

2MCBB Graduate Program, Boston University, Boston, MA 02215, USA

3Deptartment of Chemistry, Center for Molecular Discovery, Boston University, Boston, MA 02215, USA

4Department of Biology, Boston University, Boston, MA 02215, USA

Correspondence to:

Ulla Hansen, email: uhansen@bu.edu

Sriharsa Pradhan, email: pradhan@neb.com

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.


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