Regulating foxa-mediated transcription during liver development

The National Institute of Diabetes and Digestive and Kidney Diseases awarded The Medical College of Wisconsin, Inc. $406,985 on September 1, 2026, under the Diabetes, Digestive, and Kidney Diseases Extramural Research program (CFDA 93.847) to investigate mechanisms regulating FOXA1 and FOXA2 transcription factors during human liver development.

The research addresses how FOXA1 and FOXA2 pioneer transcription factors regulate chromatin opening and gene activation required for hepatic specification from human induced pluripotent stem cells. The project will identify transcriptional co-activators that fine-tune FOXA1 and FOXA2 chromatin remodeling during hepatocyte specification and determine how acetylation and sumoylation of these factors impact their ability to bind and remodel chromatin in preparation for liver gene activation. The work advances understanding of mechanisms underlying normal liver development and differentiation.

Performance occurs in Wauwatosa, Wisconsin, with a period of performance from September 1, 2026, through May 31, 2030. The award is classified as a Project Grant, a competitive research funding mechanism under the NIDDK extramural research program supporting basic and clinical biomedical research that improves understanding of disease mechanisms and leads to improved prevention, diagnosis, and treatment across diabetes, digestive, endocrine, liver, metabolic, and related disease areas.

Abstract

The goal of this proposal is to determine mechanisms of FOXA1 and 2 regulation required for the specification of hepatic fate in humans. FOXA1 and 2 are "pioneer" initial chromatin-binding transcription factors capable of opening silent compacted chromatin, remodeling underlying histone:DNA contacts, and repositioning nucleosome particles. These unique capabilities promote the binding of additional transcription factors required to regulate gene transcription. In the embryo, FOXA1 and 2 are essential for liver specification. Based upon the ability of these factors to engage specific sites in chromatin in hepatic endoderm prior to the activation of the liver gene repertoire, and to remodel target sites within compacted chromatin both in vitro and in vivo, IT is widely acknowledged that FOXA1 and 2 obligatorily direct hepatic competence through chromatin opening of a vast array of liver genes required for differentiation, metabolism, and tissue integrity. However, despite their vital contributions to the initial chromatin remodeling events required for gene activation in the newly specified liver, no extant study has directly addressed the regulation of FOXA1 and 2 function at the onset of human hepatic development. To address this deficit, we will investigate the novel hypothesis that FOXA1 and 2 chromatin binding and remodeling abilities are regulated over the course of human liver specification through a combination of 1) FOXA1 and 2-recruited CO-activators and 2) posttranslational modification of key FOXA1 and 2 functional domains. We propose to investigate this hypothesis by identifying the transcriptional CO-activators that fine-tune FOXA1 and 2 chromatin opening and remodeling during hepatocyte specification from human induced pluripotent stem cells and determining how acetylation and sumoylation of FOXA1 and 2 impacts their ability to bind and remodel chromatin preparatory to their activation of liver genes. Disruption of these same regulatory processes in the adult liver is a likely contributor to FOXA1 and 2 dysfunction in hepatic disorders and malignancy, making IT vital that we uncover the key mechanisms and players.