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. 2019 Aug 12;20(16):3918. doi: 10.3390/ijms20163918

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© 2019 by the authors.

Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).

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Epigenetic regulation of mesenchymal stem cells during adipocyte differentiation. The differentiation of mesenchymal stem cells into adipocytes is driven by cooperative transcription factors and epigenetic remodelers that act to modulate the chromatin landscape. The recruitment of early adipogenic factors such as C/EBPβ, C/EBPδ as well other transcription regulators (STAT5A, GR) to regulatory elements (enhancers) is mediated by resolving bivalent H3K4me3 and H3K9me3 marks to a monovalent active mark, H3K4me3. The early transcription factor C/EBPβ stimulates the expression of KDM4B, which in turn serves as a cofactor of C/EBPβ to facilitate the transcriptional activation of cell cycle-related genes by removing H3K9me3 marks and recruiting MLL3/4 to establish active enhancers. In addition, KDM4B and LSD1 remove H3K9me2 and H3K9me3 (deposited by SETDB1 and G9a) on C/EBPα and PPARγ loci to promote their expression, whereas Nsd2 increases H3K36me2 to activate expression of C/EBPα and others adipogenic targets of PPARγ. In addition, the interaction of KDM7 with C/EBPα leads to the removal of H3K9me2 from the promoter of PPARγ to modulate its expression and that of other adipogenesis-related genes. Together, these mechanisms contribute to shaping the chromatin landscape to induce adipocyte-specific gene expression, thus promoting the adipogenic phenotype. C/EBP: CCAT/enhancer-binding protein; GR: glucocorticoid receptor; H3K4me1: histone H3 lysine 4 monomethylation H3K4me2: histone H3 lysine 4 dimethylation; H3K4me3: histone H3 lysine 4 trimethylation; H3K9me2: histone H3 lysine 9 dimethylation; H3K9me3: histone H3 lysine 9 trimethylation; H3K36me2: histone H3 lysine 36 dimethylation; KDM: histone lysine methyltransferase; LSD1: histone lysine demethylase 1; Nsd2: nuclear receptor binding SET domain protein 2; MLL3/4: mixed-lineage leukemia 3-4; Pol II, RNA polymerase II; PPARγ: peroxisome proliferator-activated-γ; RXR: retinoid X receptor; SETDB1: SET domain bifurcated 1; STAT5A: signal transducer and activator of transcription 5A.