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HNF4 Regulates β-Oxidation and is Indispensable for Intestinal Stem Cell Renewal

33 Pages Posted: 13 Jun 2019 Sneak Peek Status: Review Complete

See all articles by Lei Chen

Lei Chen

Rutgers, The State University of New Jersey - Department of Genetics

Roshan Vasoya

Rutgers, The State University of New Jersey - Department of Genetics

Natalie Toke

Rutgers, The State University of New Jersey - Department of Genetics

Aditya Parthasarathy

Rutgers, The State University of New Jersey - Department of Genetics

Shirley Luo

Rutgers, The State University of New Jersey - Department of Genetics

Eric Chiles

Rutgers University, New Brunswick - Rutgers Cancer Institute of New Jersey

Juan Flores

Rutgers, The State University of New Jersey - Rutgers University, Newark

Nan Gao

Rutgers, The State University of New Jersey - Rutgers University, Newark

Edward Bonder

Rutgers, The State University of New Jersey - Rutgers University, Newark

Xiaoyang Su

Rutgers University, New Brunswick - Rutgers Cancer Institute of New Jersey

Michael P. Verzi

Rutgers, The State University of New Jersey - Department of Genetics

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Abstract

Intestinal stem cell (ISC) function is regulated by diet and cellular metabolism; however, regulatory mechanisms controlling ISC metabolism are not fully understood. HNF4 transcription factors are important regulators of metabolism, but their functions in ISCs are not elucidated. Here, we demonstrate that fatty acid oxidation (FAO) supports ISC renewal, and HNF4 transcription factors bind to and activate the FAO gene program. Loss of HNF4 paralogs reduces fatty acid oxidation and instead increases fatty acid synthesis. Compound mutant mice reveal that HNF4 transcription factors function redundantly to promote ISC renewal. HNF4 loss leads to reduced levels of FAO gene transcripts, FAO activity and TCA metabolites. Metabolic intervention partially restores TCA metabolites and ISC function in the absence of HNF4. These findings link core cellular transcription factor networks with metabolic state to broaden our understanding of metabolic regulation in stem cell homeostasis.

Keywords: HNF4, transcription factor, intestinal stem cell, self-renewal, fatty acid oxidation, TCA cycle, metabolic regulation

Suggested Citation

Chen, Lei and Vasoya, Roshan and Toke, Natalie and Parthasarathy, Aditya and Luo, Shirley and Chiles, Eric and Flores, Juan and Gao, Nan and Bonder, Edward and Su, Xiaoyang and Verzi, Michael P., HNF4 Regulates β-Oxidation and is Indispensable for Intestinal Stem Cell Renewal (June 13, 2019). CELL-STEM-CELL-D-19-00374. Available at SSRN: https://ssrn.com/abstract=3403334 or http://dx.doi.org/10.2139/ssrn.3403334
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Lei Chen

Rutgers, The State University of New Jersey - Department of Genetics

311 North 5th Street
New Brunswick, NJ 08854
United States

Roshan Vasoya

Rutgers, The State University of New Jersey - Department of Genetics

311 North 5th Street
New Brunswick, NJ 08854
United States

Natalie Toke

Rutgers, The State University of New Jersey - Department of Genetics

311 North 5th Street
New Brunswick, NJ 08854
United States

Aditya Parthasarathy

Rutgers, The State University of New Jersey - Department of Genetics

311 North 5th Street
New Brunswick, NJ 08854
United States

Shirley Luo

Rutgers, The State University of New Jersey - Department of Genetics

311 North 5th Street
New Brunswick, NJ 08854
United States

Eric Chiles

Rutgers University, New Brunswick - Rutgers Cancer Institute of New Jersey

195 Little Albany Street
New Brunswick, NJ 08903-2681
United States

Juan Flores

Rutgers, The State University of New Jersey - Rutgers University, Newark

180 University Avenue
Newark, NJ 07102
United States

Nan Gao

Rutgers, The State University of New Jersey - Rutgers University, Newark

180 University Avenue
Newark, NJ 07102
United States

Edward Bonder

Rutgers, The State University of New Jersey - Rutgers University, Newark

180 University Avenue
Newark, NJ 07102
United States

Xiaoyang Su

Rutgers University, New Brunswick - Rutgers Cancer Institute of New Jersey

195 Little Albany Street
New Brunswick, NJ 08903-2681
United States

Michael P. Verzi (Contact Author)

Rutgers, The State University of New Jersey - Department of Genetics ( email )

311 North 5th Street
New Brunswick, NJ 08854
United States

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