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Control of Region-Specific Intestinal Metabolism and Maintenance by PRDM16

61 Pages Posted: 3 Dec 2018 Sneak Peek Status: Under Review

See all articles by Rachel R. Stine

Rachel R. Stine

University of Pennsylvania - Department of Cell and Developmental Biology

Tara TeSlaa

Princeton University - Lewis-Sigler Institute for Integrative Genomics

Megan Kissig

University of Pennsylvania - Department of Cell and Developmental Biology

Zachary E. Stine

University of Pennsylvania, The Wistar Institute of Anatomy and Biology

Chan Wook Kwon

University of Pennsylvania - Department of Cell and Developmental Biology

Hee-Woong Lim

University of Pennsylvania - Institute for Diabetes, Obesity and Metabolism

Klaus H. Kaestner

University of Pennsylvania - Institute for Diabetes, Obesity and Metabolism

Joshua D. Rabinowitz

Princeton University - Lewis-Sigler Institute for Integrative Genomics

Patrick Seale

University of Pennsylvania - Department of Cell and Developmental Biology

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Abstract

Distinct metabolic programs regulate intestinal stem cell renewal and differentiation. However, the mechanisms that rewire metabolism during differentiation are poorly defined. It is also unclear whether progenitors in different intestinal regions utilize specialized metabolic programs. Here, we identify the transcription factor PRDM16 as a critical region-specific regulator of small intestinal metabolism and progenitor differentiation. Acute deletion of Prdm16 in mice causes severe intestinal atrophy, apoptosis, and an accumulation of poorly differentiated cells. Genomic and metabolic studies show that PRDM16 controls the levels of fatty acid oxidation (FAO) within the stem cell niche. Notably, PRDM16 levels and FAO are highest in the upper small intestine and decline distally. Accordingly, deletion of Prdm16 or inhibition of FAO selectively impairs the differentiation of upper-intestinal enteroid cultures. Collectively, these data reveal that PRDM16 specifies a region-specific FAO metabolic switch in intestinal progenitor cells to maintain tissue homeostasis.

Suggested Citation

Stine, Rachel R. and TeSlaa, Tara and Kissig, Megan and Stine, Zachary E. and Kwon, Chan Wook and Lim, Hee-Woong and Kaestner, Klaus H. and Rabinowitz, Joshua D. and Seale, Patrick, Control of Region-Specific Intestinal Metabolism and Maintenance by PRDM16 (November 30, 2018). Available at SSRN: https://ssrn.com/abstract=3293687 or http://dx.doi.org/10.2139/ssrn.3293687
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Rachel R. Stine

University of Pennsylvania - Department of Cell and Developmental Biology ( email )

3400 Civic Center Blvd
Philadelphia, PA 19104
United States

Tara TeSlaa

Princeton University - Lewis-Sigler Institute for Integrative Genomics

Carl Icahn Laboratory
Princeton, NJ 08544
United States

Megan Kissig

University of Pennsylvania - Department of Cell and Developmental Biology

3400 Civic Center Blvd
Philadelphia, PA 19104
United States

Zachary E. Stine

University of Pennsylvania, The Wistar Institute of Anatomy and Biology

3601 Spruce Street
Philadelphia, PA
United States

Chan Wook Kwon

University of Pennsylvania - Department of Cell and Developmental Biology

3400 Civic Center Blvd
Philadelphia, PA 19104
United States

Hee-Woong Lim

University of Pennsylvania - Institute for Diabetes, Obesity and Metabolism

Philadelphia, PA 19104
United States

Klaus H. Kaestner

University of Pennsylvania - Institute for Diabetes, Obesity and Metabolism

Philadelphia, PA 19104
United States

Joshua D. Rabinowitz

Princeton University - Lewis-Sigler Institute for Integrative Genomics

Carl Icahn Laboratory
Princeton, NJ 08544
United States

Patrick Seale (Contact Author)

University of Pennsylvania - Department of Cell and Developmental Biology ( email )

3400 Civic Center Blvd
Philadelphia, PA 19104
United States

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