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Cell Stem Cell. 2019 Sep 21. pii: S1934-5909(19)30384-4. doi: 10.1016/j.stem.2019.08.017. [Epub ahead of print]

PRDM16 Maintains Homeostasis of the Intestinal Epithelium by Controlling Region-Specific Metabolism.

Author information

1
Institute for Diabetes, Obesity & Metabolism, Smilow Center for Translational Research, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Cell and Developmental Biology, Smilow Center for Translational Research, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: stiner@pennmedicine.upenn.edu.
2
Institute for Diabetes, Obesity & Metabolism, Smilow Center for Translational Research, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Cell and Developmental Biology, Smilow Center for Translational Research, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
3
Lewis-Sigler Institute for Integrative Genomics and Department of Chemistry, Princeton University, Princeton, NJ 08544, USA.
4
Wistar Institute, Philadelphia, PA 19104, USA.
5
Institute for Diabetes, Obesity & Metabolism, Smilow Center for Translational Research, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
6
Department of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
7
Institute for Diabetes, Obesity & Metabolism, Smilow Center for Translational Research, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Genetics, Smilow Center for Translational Research, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
8
Institute for Diabetes, Obesity & Metabolism, Smilow Center for Translational Research, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Cell and Developmental Biology, Smilow Center for Translational Research, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: sealep@pennmedicine.upenn.edu.

Abstract

Metabolic pathways dynamically regulate tissue development and maintenance. However, the mechanisms that govern the metabolic adaptation of stem or progenitor cells to their local niche are poorly understood. Here, we define the transcription factor PRDM16 as a region-specific regulator of intestinal metabolism and epithelial renewal. PRDM16 is selectively expressed in the upper intestine, with enrichment in crypt-resident progenitor cells. Acute Prdm16 deletion in mice triggered progenitor apoptosis, leading to diminished epithelial differentiation and severe intestinal atrophy. Genomic and metabolic analyses showed that PRDM16 transcriptionally controls fatty acid oxidation (FAO) in crypts. Expression of this PRDM16-driven FAO program was highest in the upper small intestine and declined distally. Accordingly, deletion of Prdm16 or inhibition of FAO selectively impaired the development and maintenance of upper intestinal enteroids, and these effects were rescued by acetate treatment. Collectively, these data reveal that regionally specified metabolic programs regulate intestinal maintenance.

KEYWORDS:

PRDM16; apoptosis; differentiation; duodenum; fatty acid oxidation; intestinal stem cell; intestine; metabolism; transit amplifying cell

PMID:
31564549
DOI:
10.1016/j.stem.2019.08.017

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