AFF4 regulates cellular adipogenic differentiation via targeting autophagy

Yaqian Chen; Qiwen Li; Yuting Liu; Xuelan Chen; Shuang Jiang; Weimin Lin; Yuning Zhang; Rui Liu; Bin Shao; Chong Chen; Quan Yuan; Chenchen Zhou

doi:10.1371/journal.pgen.1010425

AFF4 regulates cellular adipogenic differentiation via targeting autophagy

PLoS Genet. 2022 Sep 23;18(9):e1010425. doi: 10.1371/journal.pgen.1010425. eCollection 2022 Sep.

Authors

Yaqian Chen¹, Qiwen Li¹, Yuting Liu¹, Xuelan Chen², Shuang Jiang¹, Weimin Lin¹, Yuning Zhang¹, Rui Liu¹, Bin Shao¹, Chong Chen², Quan Yuan¹, Chenchen Zhou¹

Affiliations

¹ State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China.
² Department of Hematology, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adipogenesis* / genetics
Animals
Autophagy / genetics
Autophagy-Related Proteins / genetics
Cell Differentiation / genetics
Humans
Mice
RNA Polymerase II
Transcription Factors
Transcriptional Elongation Factors / genetics
Transcriptional Elongation Factors / metabolism*

Substances

AFF4 protein, human
Aff4 protein, mouse
Autophagy-Related Proteins
Transcription Factors
Transcriptional Elongation Factors
RNA Polymerase II

Grants and funding

This work is supported from the National Natural Science Foundation of China for Quan Yuan and Chenchen Zhou (Grant Number: 82222015 to CCZ, 82125006 to QY, 82171001 to CCZ, 81901040 to CCZ) and Young Elite Scientist Sponsorship Program by China Association for Science and Technology (2020QNR001 to CCZ). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.