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

TitlePRDM16 Maintains Homeostasis of the Intestinal Epithelium by Controlling Region-Specific Metabolism.
Publication TypeJournal Article
Year of Publication2019
AuthorsStine, RR, Sakers, AP, TeSlaa, T, Kissig, M, Stine, ZE, Kwon, CWook, Cheng, L, Lim, H-W, Kaestner, KH, Rabinowitz, JD, Seale, P
JournalCell Stem Cell
Volume25
Issue6
Pagination830-845.e8
Date Published2019 12 05
ISSN1875-9777
KeywordsAnimals, Blotting, Western, Cell Differentiation, Chromatin Immunoprecipitation, DNA-Binding Proteins, Female, Flow Cytometry, Fluorescent Antibody Technique, Homeostasis, Intestinal Mucosa, Male, Mass Spectrometry, Mice, Stem Cells, Transcription Factors
Abstract

<p>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.</p>

DOI10.1016/j.stem.2019.08.017
Alternate JournalCell Stem Cell
PubMed ID31564549
PubMed Central IDPMC6898778
Grant ListF32 DK105743 / DK / NIDDK NIH HHS / United States
R01 DK103008 / DK / NIDDK NIH HHS / United States
R01 DK107589 / DK / NIDDK NIH HHS / United States
P30 DK019525 / DK / NIDDK NIH HHS / United States
T32 GM008216 / GM / NIGMS NIH HHS / United States
R01 DK123356 / DK / NIDDK NIH HHS / United States