Abstract
DNA methylation is a crucial epigenetic modification in the establishment of cell-type-specific characteristics. However, how DNA methylation is selectively reprogrammed at adipocyte-specific loci during adipogenesis remains unclear. Here, we show that the transcription factor, C/EBPδ, and the DNA methylation eraser, TET3, cooperatively control adipocyte differentiation. We perform whole-genome bisulfite sequencing to explore the dynamics and regulatory mechanisms of DNA methylation in adipocyte differentiation. During adipogenesis, DNA methylation selectively decreases at adipocyte-specific loci carrying the C/EBP binding motif, which correlates with the activity of adipogenic promoters and enhancers. Mechanistically, we find that C/EBPδ recruits a DNA methylation eraser, TET3, to catalyse DNA demethylation at the C/EBP binding motif and stimulate the expression of key adipogenic genes. Ectopic expression of TET3 potentiates in vitro and in vivo adipocyte differentiation and recovers downregulated adipogenic potential, which is observed in aged mice and humans. Taken together, our study highlights how targeted reprogramming of DNA methylation through cooperative action of the transcription factor C/EBPδ, and the DNA methylation eraser TET3, controls adipocyte differentiation.
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Data availability
WGBS of 3T3-L1 preadipocytes and adipocytes (GEO accession no. GSE186340), Bulk RNA-seq data of 3T3-L1 preadipocytes and adipocytes (GEO accession no. GSE185493), Bulk RNA-seq data of 3T3-L1 (ref. 21, GEO accession no. GSE95533), scRNA-seq data of ASCs (BioProject accession no. PRJNA708350), scRNA-seq data of SVCs (ref. 29; GEO accession no. GSE160729), PCHi-C (ref. 21, GEO accession no. GSE95533), ChIP–seq data73, GEO accession no. GSE56872), GTEx data (GTEX, https://www.gtexportal.org/home/). All scripts and codes are found under https://github.com/dohlee/adipogenesis-methylation. Source data are provided with this paper.
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Acknowledgements
We thank K. Fujiki and M. Murata for providing the TET2 and TET3 vectors. This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT; no. NRF-2018R1A5A1024340 to J.B.K. and J.P., 2020R1A3B2078617 to J.B.K. and NRF-2018R1A5A2024425 to S.H.C.).
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J.P. conceptualized the study, performed the experiments, analysed the data and wrote the manuscript. D.H.L., S.J.H., T.Y.R. and S.K. analysed the WGBS and RNA-seq data. D.H.L. performed a combined analysis of WGBS, PCHi-C and RNA-seq data. J.O. and J.P. provided the adipocyte lineage-tracing mice. J.R.N. and C.H.L. provided aged mice. Y.K.L. and S.H.C. performed the experiments on human adipose tissue. Y.J.P., G.L., S.M.H., J.S.H., Y.Y.K., Y.G.J., H.N., K.C.S. and S.M.K., conducted the animal experiments. J.B.K. supervised the study and wrote the manuscript.
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Extended data
Extended Data Fig. 1
a, FPKM of Dlk1 in pre-AD and AD (n = 3). b, Microscopic images of pre-AD and AD used for RNA-seq and WGBS analyzes. c,d, The degrees of DNA methylation of pre-AD and AD were analyzed using several criteria. The median is shown as the center line in the boxes. The first or third quartile where 25% or 75% of the data are below is represented by the line at the bottom or top of the box. DNA methylation was analyzed based on SINE, LINE, LTR (c), satellite, RNA, and other regions (d). The median is shown as the center line in the boxes (c,d). SINE, n = 884915; LINE n = 625222; LTR n = 597813; DNA, n = 95333. Satellite, n = 9599; RNA n = 8908; Other, n = 11517. The first or third quartile where 25% or 75% of the data are below is represented by the line at the bottom or top of the box (c,d). e, Absolute changes in DNA methylation of hypo-DMRs (green) and hyper-DMRs (brown). f, Kyoto Encyclopedia of Genes and Genomes pathway associated with DNA methylation changes. All data represent mean ± SEM (a). Two tailed Student’s t-test (a).
Extended Data Fig. 2 The mean DNA methylation around several motifs. Related to Fig. 2.
a,b, The levels of DNA methylation in promoters and enhancers around several transcription factor binding motifs. The X-axis is the distance from the center of each motif. The Y-axis represents the mean of DNA methylation. c, Examples of genes having interactions between promoters and enhancers with hypo-DMRs and the C/EBP binding motif.
Extended Data Fig. 3 Transcript and DNA methylation changes associated with DNA methylation enzymes in several models of AD. Related to Fig. 3.
a, Relative mRNA levels of the DNA methyltransferase (DNMT) family in 3T3-L1 pre-AD and AD (n = 3). b, Relative mRNA expression of adipogenic genes, TET family, and DNMT family in fibro-adipogenic progenitors (FAPs) and AD from published scRNA-seq data (Sarvari et al., 2021, GSE160729). c–g, Expression levels of Pparg2 (c), Cd36 (d), Dnmt1 (e), Dnmt3a (f), and Dnmt3b (g) on a UMAP plot from published scRNA-seq data (Sarvari et al., 2021, GSE160729). h–j, Representative genome browser view showing DNA methylation Pparg2 (h), Adipoq (i), and Fabp4 (j) in AD of WT (violet) and AD-specific Dnmt1 KO male mice (Dnmt AKO) (purple). k, Relative mRNA of the TET family in 3T3-L1 pre-AD and AD during adipogenesis. Data from GSE56872 (n = 2). All data represent mean ± SEM. Two-way ANOVA with Tukey post hoc test (a,k).
Extended Data Fig. 4 The roles of TET protein in adipogenic gene regulation. Related to Fig. 3.
a, Relative enrichment of TET3 binding to the Glut1 promoter (n = 4). b–d, Relative mRNA levels of Tet3 (b), Pparg2 (c), and Cebpa (d) (n = 3). e–g, Relative enrichment of TET2 binding at Pparg2 (e), Adipoq (f), and Glut1 (g) promoters in 3T3-L1 AD. h,i, Relative mRNA levels of TET family (h) and adipogenic genes (i) such as Pparg2, Adipoq, Cebpa, Cd36, and Fabp4 in mock or TET2 overexpressed 3T3-L1 pre-AD (n = 6). All data represent mean ± SEM. n.s., not significant. Two-tailed Student’s t-test (b–d, h–i).
Extended Data Fig. 5 The relationship between C/EBPβ, TET3, and methylated DNA. Related to Fig. 4.
a, ChIP-qPCR of C/EBPα at the Pparg2 promoter during adipogenesis (n = 2). b, Co-immunoprecipitation. HEK293T cells were transfected with TET3 and/or C/EBPδ expression vectors. Co-immunoprecipitation and western blotting were performed with the indicated antibodies. IP, immunoprecipitation. c, The mRNA levels of Cebpd and Tet3 (n = 4). d, 3T3-L1 preadipocytes were transfected with siRNAs. After 2 days of contact inhibition, ChIP-qPCR was performed. Relative enrichment of TET3 at the Pparg2 and Adipoq promoters (n = 3). e, Relative mRNA levels of Cebpd after treatment with dexamethasone (DEXA) (n = 3). f, Knockdown efficiency of Cebpb (n = 3). g, Relative enrichment of TET3 at the Pparg2 and Adipoq promoters (n = 3). h, Electrophoretic mobility shift assay in which radioisotope-labeled hot DNA (C/EBP response element, C/EBP RE) and C/EBPβ were co-incubated. Unlabeled CH3-CEBP RE, Srebp1c RE (SRE), and PPAR RE (PPRE) were used as binding competitors for C/EBPβ as cold DNA. All data represent mean ± SEM. n.s., not significant. Two-tailed Student’s t-test (a, c–g). The blue dotted line is the IgG control.
Extended Data Fig. 6 scRNA data of ASCs isolated from eWAT and iWAT. Related to Fig. 5.
Single-cell RNA sequencing was performed in adipose stem cells (ASCs; CD31−/CD45−) isolated from eWAT and iWAT (PRJNA708350). a, Transcript levels of the adipogenic genes of ASCs in eWAT and iWAT. b, Transcript levels of the TET family of ASCs in eWAT and iWAT. c, Transcript levels of the DNMT family of ASCs in eWAT and iWAT. d, The levels of 5mC in CD45+ cells from pgWAT and iWAT of male and female mice (n = 4). n.s., not significant. Significance was determined using the Wilcoxon rank sum test in ‘FindMarkers’ function of Seurat (PMID: 31178118) (a–c). All data represent mean ± SEM (d). Two-way ANOVA with Tukey post hoc test (d).
Extended Data Fig. 7 The effects of Tet3 suppression in iWAT.
a, Experimental scheme. siNC or siTet3 was injected into the left or right fat pads of 8-week-old WT male mice, respectively. b–d, The mRNA levels of Tet3 (b), adipogenic genes such as Cebpa, Adipoq, Plin1, Cebpb, and Cebpd (c,d) (n = 4). e, Histological analysis of iWAT after siNC or siTet3 administration (siNC n = 4, siTet3 n = 4). Scale bar, 100 mm. n.s., not significant (Student’s t-test). f, Quantification of adipocyte size of siNC or siTet3-administrated iWAT (siNC n = 1,310, siTet3 n = 1,523). Two adipose tissue images from each mouse were quantified. Two-tailed Student’s t-test (b–d, f).
Extended Data Fig. 8 During human aging, adipogenic potential is reduced in subcutaneous adipose tissue. Related to Fig. 6.
The GTEx data (https://gtexportal.org) were used to analyze transcript changes according to human aging. Human subcutaneous adipose tissue and visceral adipose tissue data were reprocessed with age. a–c, Transcript changes in adipogenic genes, such as PPARG (a), CEBPA (b), and FABP4 (c) in subcutaneous adipose tissue. 20–29, n = 32; 30–39, n = 38, 40–49, n = 74; 50–59, n = 149; 60–69, n = 136; 70–79, n = 13. d–f, Transcript changes in adipogenic genes, such as PPARG (d), CEBPA (e), and FABP4 (f) in visceral adipose tissue. 20–29, n = 25; 30–39, n = 28, 40–49, n = 57; 50–59, n = 124; 60–69, n = 109; 70–79, n = 12. All data are presented as the mean ± SEM. n.s., not significant (one-way ANOVA with Tukey’s post hoc test).
Extended Data Fig. 9 Several phenotypes of aged male mice, compared to young male mice. Related to Fig. 6.
a, Body weights of young and aged male mice (n = 6). b,c, Mass of subcutaneous (b) and visceral adipose tissue (c) (n = 6). d, e, iWAT (d) and eWAT mass (e) of aged male mice overexpressing mock or TET3 (n = 9). f, Insulin-independent glucose uptake. All data represent mean ± SEM. n.s., not significant. Two-tailed Student’s t-test (a–c).
Extended Data Fig. 10 TET2 overexpression does not recover the decrease in adipogenic capacity with aging. Related to Fig. 6.
a, Experimental scheme for TET2 overexpression in C57BL/6J aged male mice. TET2 was overexpressed in the right fat pad of aged mice, and the left fat pad was injected with the mock vector as a control. b, Picture of subcutaneous adipose tissue of aged mice overexpressing mock or TET2. c,d, The transcript levels of Tet2 (c) and adipogenic genes (d) in iWAT of TET2 overexpressed mice (mock n = 5, TET3 n = 6). All data are presented as the mean ± SEM. n.s., not significant. Two-tailed Student’s t-test (c–d).
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Supplementary Fig. 1 FACS gating strategy
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Park, J., Lee, D.H., Ham, S. et al. Targeted erasure of DNA methylation by TET3 drives adipogenic reprogramming and differentiation. Nat Metab 4, 918–931 (2022). https://doi.org/10.1038/s42255-022-00597-7
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DOI: https://doi.org/10.1038/s42255-022-00597-7
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