In:
PLOS Genetics, Public Library of Science (PLoS), Vol. 18, No. 9 ( 2022-9-23), p. e1010425-
Abstract:
Transcriptional elongation is a universal and critical step during gene expression. The super elongation complex (SEC) regulates the rapid transcriptional induction by mobilizing paused RNA polymerase II (Pol II). Dysregulation of SEC is closely associated with human diseases. However, the physiological role of SEC during development and homeostasis remains largely unexplored. Here we studied the function of SEC in adipogenesis by manipulating an essential scaffold protein AF4/FMR2 family member 4 (AFF4), which assembles and stabilizes SEC. Knockdown of AFF4 in human mesenchymal stem cells (hMSCs) and mouse 3T3-L1 preadipocytes inhibits cellular adipogenic differentiation. Overexpression of AFF4 enhances adipogenesis and ectopic adipose tissue formation. We further generate Fabp4-cre driven adipose-specific Aff4 knockout mice and find that AFF4 deficiency impedes adipocyte development and white fat depot formation. Mechanistically, we discover AFF4 regulates autophagy during adipogenesis. AFF4 directly binds to autophagy-related protein ATG5 and ATG16L1, and promotes their transcription. Depleting ATG5 or ATG16L1 abrogates adipogenesis in AFF4-overepressing cells, while overexpression of ATG5 and ATG16L1 rescues the impaired adipogenesis in Aff4 -knockout cells. Collectively, our results unveil the functional importance of AFF4 in regulating autophagy and adipogenic differentiation, which broaden our understanding of the transcriptional regulation of adipogenesis.
Type of Medium:
Online Resource
ISSN:
1553-7404
DOI:
10.1371/journal.pgen.1010425
DOI:
10.1371/journal.pgen.1010425.g001
DOI:
10.1371/journal.pgen.1010425.g002
DOI:
10.1371/journal.pgen.1010425.g003
DOI:
10.1371/journal.pgen.1010425.g004
DOI:
10.1371/journal.pgen.1010425.g005
DOI:
10.1371/journal.pgen.1010425.g006
DOI:
10.1371/journal.pgen.1010425.s001
DOI:
10.1371/journal.pgen.1010425.s002
DOI:
10.1371/journal.pgen.1010425.s003
DOI:
10.1371/journal.pgen.1010425.s004
DOI:
10.1371/journal.pgen.1010425.s005
DOI:
10.1371/journal.pgen.1010425.s006
DOI:
10.1371/journal.pgen.1010425.s007
DOI:
10.1371/journal.pgen.1010425.s008
Language:
English
Publisher:
Public Library of Science (PLoS)
Publication Date:
2022
detail.hit.zdb_id:
2186725-2
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