Critical roles of transcriptional coactivator MED1 in the formation and function of mouse adipose tissues

Abstract

The MED1 subunit has been shown to mediate ligand-dependent binding of the Mediator coactivator complex to multiple nuclear receptors, including the adipogenic PPARγ, and to play an essential role in ectopic PPARγ-induced adipogenesis of mouse embryonic fibroblasts. However, the precise roles of MED1, and its various domains, at various stages of adipogenesis and in adipose tissue have been unclear. Here, after establishing requirements for MED1, including specific domains, for differentiation of 3T3L1 cells and both primary white and brown preadipocytes, we used multiple genetic approaches to assess requirements for MED1 in adipocyte formation, maintenance, and function in mice. We show that MED1 is indeed essential for the differentiation and/or function of both brown and white adipocytes, as its absence in these cells leads to, respectively, defective brown fat function and lipodystrophy. This work establishes MED1 as an essential transcriptional coactivator that ensures homeostatic functions of adipocytes.

MED1 IDR acetylation reorganizes the transcription preinitiation complex, rewires 3D chromatin interactions and reprograms gene expression

“…Therefore, the Mediator is posited at the interface between linear and spatial chromatin functions to drive gene activation. While not generally required for cell viability 45 , the ubiquitously expressed MED1 Mediator subunit is frequently monitored as a surrogate for Mediator and has been reported to have an essential role in transcription in certain cell types that include ER + BC cells 3,46–48 . Consistent with the observation that histone modifying factors also functionally modify many transcriptional (co)activators 49 , we report that MED1 is acetylated with 6 major acetylation sites mapped to the IDR.…”

Genetically Engineered Mice Unveil In Vivo Roles of the Mediator Complex

“…Although embryonic adipocytes and skeletal muscle formed successfully in the absence of MED1, pups died shortly around the weaning age, possibly due to defects in skeletal muscle or in the parts of the brain originating from Myf5 expressing cells [62] caused by nonspecific activation. Ucp1, Dio2, and Cox8b genes commonly expressed in active BAT were strikingly down-regulated in knockout mice [48].…”

“…White (WAT) and brown (BAT) adipose tissues responded differently to the Mediator components deficiency. Due to the inability of Med subunit knockout adipose tissue to store lipids (absorbed or de novo synthesized) and grow, they become deposited ectopically in the liver, as observed in Med1-adipoq and Med19 knockouts [48,56]. Thus, the phenotypes of LKO and AKO mice can sometimes be opposed regarding liver pathology.…”

Inflammation‐mediated metabolic regulation in adipose tissue

“…For example, mediator complex subunit 1 (MED1) is a key component of the complex that interacts with nuclear receptors. It is a transcriptional coactivator that is essential for the formation, differentiation, and function of adipose tissue, 154,155 and the knockdown of MED1 in hepatocytes reduces autophagy; impairs FAO; and affects the activities of several nuclear receptors and transcription factors, including PPARγ and FOXO1. 156 In addition, thioredoxin-interacting proteins (TXNIP/VDUP1) are key mediators of cellular stress responses.…”