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MED1 is a lipogenesis coactivator required for postnatal adipose expansion.

ABSTRACT: MED1 often serves as a surrogate of the general transcription coactivator complex Mediator for identifying active enhancers. MED1 is required for phenotypic conversion of fibroblasts to adipocytes in vitro, but its role in adipose development and expansion in vivo has not been reported. Here, we show that MED1 is not generally required for transcription during adipogenesis in culture and that MED1 is dispensable for adipose development in mice. Instead, MED1 is required for postnatal adipose expansion and the induction of fatty acid and triglyceride synthesis genes after pups switch diet from high-fat maternal milk to carbohydrate-based chow. During adipogenesis, MED1 is dispensable for induction of lineage-determining transcription factors (TFs) PPARγ and C/EBPα but is required for lipid accumulation in the late phase of differentiation. Mechanistically, MED1 controls the induction of lipogenesis genes by facilitating lipogenic TF ChREBP- and SREBP1a-dependent recruitment of Mediator to active enhancers. Together, our ﬁndings identify a cell- and gene-specific regulatory role of MED1 as a lipogenesis coactivator required for postnatal adipose expansion.

SUBMITTER: Jang Y

PROVIDER: S-EPMC8091974 | biostudies-literature | 2021 May

REPOSITORIES: biostudies-literature

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MED1 is a lipogenesis coactivator required for postnatal adipose expansion.

Jang Younghoon Y Park Young-Kwon YK Lee Ji-Eun JE Wan Danyang D Tran Nhien N Gavrilova Oksana O Ge Kai K

Genes & development 20210422 9-10

MED1 often serves as a surrogate of the general transcription coactivator complex Mediator for identifying active enhancers. MED1 is required for phenotypic conversion of fibroblasts to adipocytes in vitro, but its role in adipose development and expansion in vivo has not been reported. Here, we show that MED1 is not generally required for transcription during adipogenesis in culture and that MED1 is dispensable for adipose development in mice. Instead, MED1 is required for postnatal adipose exp ...[more]

PMID: 33888555

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Project description:UnlabelledPeroxisome proliferator-activated receptor-γ (PPARγ), a nuclear receptor, when overexpressed in liver stimulates the induction of adipocyte-specific and lipogenesis-related genes and causes hepatic steatosis. We report here that Mediator 1 (MED1; also known as PBP or TRAP220), a key subunit of the Mediator complex, is required for high-fat diet-induced hepatic steatosis as well as PPARγ-stimulated adipogenic hepatic steatosis. Mediator forms the bridge between transcriptional activators and RNA polymerase II. MED1 interacts with nuclear receptors such as PPARγ and other transcriptional activators. Liver-specific MED1 knockout (MED1(ΔLiv) ) mice, when fed a high-fat (60% kcal fat) diet for up to 4 months failed to develop fatty liver. Similarly, MED1(ΔLiv) mice injected with adenovirus-PPARγ (Ad/PPARγ) by tail vein also did not develop fatty liver, whereas mice with MED1 (MED1(fl/fl) ) fed a high-fat diet or injected with Ad/PPARγ developed severe hepatic steatosis. Gene expression profiling and northern blot analyses of Ad/PPARγ-injected mouse livers showed impaired induction in MED1(ΔLiv) mouse liver of adipogenic markers, such as aP2, adipsin, adiponectin, and lipid droplet-associated genes, including caveolin-1, CideA, S3-12, and others. These adipocyte-specific and lipogenesis-related genes are strongly induced in MED1(fl/fl) mouse liver in response to Ad/PPARγ. Re-expression of MED1 using adenovirally-driven MED1 (Ad/MED1) in MED1(ΔLiv) mouse liver restored PPARγ-stimulated hepatic adipogenic response. These studies also demonstrate that disruption of genes encoding other coactivators such as SRC-1, PRIC285, PRIP, and PIMT had no effect on hepatic adipogenesis induced by PPARγ overexpression.ConclusionWe conclude that transcription coactivator MED1 is required for high-fat diet-induced and PPARγ-stimulated fatty liver development, which suggests that MED1 may be considered a potential therapeutic target for hepatic steatosis. (HEPATOLOGY 2011;).

Project description:Background/Objectives: Estrogen receptor-α coactivator MED1 is overexpressed in 40-60% of human breast cancers, and its high expression correlates with poor disease-free survival of patients undergoing anti-estrogen therapy. However, the molecular mechanism underlying MED1 upregulation and activation in breast cancer treatment resistance remains elusive. Methods: miRNA and mRNA expression analysis was performed using the NCBI GEO database. MED1 targeting and its impact on therapy resistance was evaluated in control and tamoxifen-resistant breast cancer cell lines by miR-205 overexpression and inhibition. Immunoblotting, chromatin immunoprecipitation, and luciferase reporter assays were used to understand the molecular mechanism of MED1-mediated tamoxifen resistance. Mice xenograft models were used to validate treatment efficacy and molecular mechanisms in vivo. Results: miR-205 was found to directly target and suppress the expression of MED1 through bioinformatic analyses and experimental validations. An inverse correlation of miR-205 and MED1 was observed in breast cancer patients with high MED1/low miR-205, indicative of poor prognosis in long-term anti-estrogen treatment. Furthermore, the depletion of miR-205 was observed in tamoxifen-resistant breast cancer cells overexpressing MED1. The restoration of miR-205 expression attenuated MED1 expression and re-sensitized cells to tamoxifen both in vitro and in vivo. Interestingly, miR205 was also found to target another key regulatory gene, HER3, which drives PI3K/Akt signaling and MED1 activation by phosphorylation. Importantly, we found ER target gene transcription and promoter cofactor recruitment by tamoxifen can be reversed by induced miR205 expression. Conclusions: Altogether, miR-205 functions as a negative regulator of MED1 and HER3, affecting the regulation of the HER3-PI3K/Akt-MED1 axis in anti-estrogen resistance, and could serve as a potential therapeutic regime to overcome treatment resistance.

Dataset Information

MED1 is a lipogenesis coactivator required for postnatal adipose expansion.

Publications

MED1 is a lipogenesis coactivator required for postnatal adipose expansion.

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