Targeted erasure of DNA methylation by TET3 drives adipogenic reprogramming and differentiation

Park, Jeu; Lee, Dohoon; Ham, Seokjin; Oh, Jiyoung; Noh, Jung‐Ran; Lee, Yun Kyung; Park, Yoon Jeong; Lee, Gung; Han, Sun-Hee; Han, Joo Seok; Kim, Ye Young; Jeon, Yong Geun; Nahmgoong, Han; Shin, Kyung Cheul; Kim, Sung Min; Choi, Sung Hee; Lee, Chul‐Ho; Park, Jiyoung; Roh, Tae-Young; Kim, Sun; Kim, Jae Bum

doi:10.1038/s42255-022-00597-7

Cited by 17 publications

(27 citation statements)

References 73 publications

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“…In contrast, higher DNA methylation was observed in gene body regions (Figure 1F), a common feature observed in various cell types[18][19][42]. We compared in-house (NABI dataset) WGBS data analysis with the adipogenic reprogramming dataset[43] to validate our WGBS data further (supplementary data depicting comparative analysis and correlation analysis between AR and NABI datasets Table S3, Figure S6, Figure S7, Figure S8, Table S4). The genome-wide distribution of DNA methylation exhibited similar patterns before and after the differentiation of adipocytes[44].…”

Section: Resultsmentioning

confidence: 99%

“…This analysis revealed specific components that play a role in adipogenesis. Among the top 20 significant pathways of DEGs, the most prominent enrichments were observed in metabolic pathways, lipid biosynthesis, and the steroid metabolism pathway [43]. On the other hand, the TNF signalling pathway, hedgehog signalling pathway, insulin secretion, protein digestion and absorption, signalling pathways regulating pluripotency of stem cells, and Wnt signalling pathway were predominantly enriched (Figure 7B).…”

Section: Kegg Pathway Analysis Of Degsmentioning

confidence: 99%

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WGBS of Differentiating Adipocytes Reveals Variations in DMRs and Context-Dependent Gene Expression

Yadav,

Singh,

Mantri

et al. 2024

Preprint

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Obesity, characterised by the accumulation of excess fat, is a complex condition resulting from the combination of genetic and epigenetic factors. Recent studies have found correspondence between DNA methylation and cell differentiation, suggesting a role of the former in cell fate determination. There is a lack of comprehensive understanding concerning the underpinnings of preadipocyte differentiation, specifically when cells are undergoing terminal differentiation (TD). To gain insight into dynamic genome-wide methylation, 3T3 L1 preadipocyte cells were differentiated by a hormone cocktail. The genomic DNA was isolated from undifferentiated cells and 4 hrs (4H), 2 days (2D) post-differentiated cells, and 15 days (15D) TD cells. We employed whole-genome bisulfite sequencing (WGBS) to ascertain global genomic DNA methylation alterations at single base resolution as preadipocyte cells differentiate. The genome-wide distribution of DNA methylation showed similar overall patterns in pre- and post- and terminally differentiated adipocytes, according to WGBS analysis. DNA methylation decreases at 4H after differentiation initiation, followed by methylation gain as cells approach TD. Studies revealed novel differentially methylated regions (DMRs) associated with adipogenesis. DMR analysis suggested that though DNA methylation is global, noticeable changes are observed at specific sites known as ‘hotspots.’ Hotspots are genomic regions rich in transcription factor (TF) binding sites and exhibit methylation-dependent TF binding. Subsequent analysis indicated hotspots as part of DMRs. The gene expression profile of key adipogenic genes in differentiating adipocytes is context-dependent, as we found a direct and inverse relationship between promoter DNA methylation and gene expression.

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Section: Resultsmentioning

confidence: 99%

Section: Kegg Pathway Analysis Of Degsmentioning

confidence: 99%

WGBS of Differentiating Adipocytes Reveals Variations in DMRs and Context-Dependent Gene Expression

Yadav,

Singh,

Mantri

et al. 2024

Preprint

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“…The lipogenic transcription factors peroxisome proliferation‐associated receptor γ (PPARγ) and CCAAT/enhancer‐binding protein (C/EBP) α have been reported to inhibit the osteogenic differentiation of BMSCs. In contrast, in aged mice and humans, Park et al 48 revealed that C/EBPδ recruits the DNA methylation eraser ten‐eleven translocation 3 (TET3) to catalyze DNA demethylation on C/EBP‐binding motifs, thus stimulating the expression of key lipogenic genes, which in turn promotes the lipogenic differentiation of BMSCs. Li et al 8 studied the upstream of PPARγ and C/EBP and found that Foxp1 inhibits the expression of PPARγ.…”

Section: Dna Methylationmentioning

confidence: 99%

Role of epigenetic regulatory mechanisms in age‐related bone homeostasis imbalance

Zhong,

Zhou,

Pan

et al. 2024

The FASEB Journal

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Alterations to the human organism that are brought about by aging are comprehensive and detrimental. Of these, an imbalance in bone homeostasis is a major outward manifestation of aging. In older adults, the decreased osteogenic activity of bone marrow mesenchymal stem cells and the inhibition of bone marrow mesenchymal stem cell differentiation lead to decreased bone mass, increased risk of fracture, and impaired bone injury healing. In the past decades, numerous studies have reported the epigenetic alterations that occur during aging, such as decreased core histones, altered DNA methylation patterns, and abnormalities in noncoding RNAs, which ultimately lead to genomic abnormalities and affect the expression of downstream signaling osteoporosis treatment and promoter of fracture healing in older adults. The current review summarizes the impact of epigenetic regulation mechanisms on age‐related bone homeostasis imbalance.

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“…Mechanistically, TET3 appears to be recruited to specific gene loci by transcription factors since TET3 has no DNA-binding specificity itself 12 . Indeed, TET3 has been described to be recruited to certain lineage-associated genomic loci via interaction with FOXA2 and C/EBP𝛿 12,14 , to catalyze DNA demethylation and stimulate the expression of key genes, thus controlling cell differentiation. It has also been hypothesized that an increase in DNA hydroxymethylation levels might enhance chromatin accessibility and binding of key lineage specific transcription factors 13 .…”

Section: Introductionmentioning

confidence: 99%

“…TET3 deficiency provokes developmental defects in multiple cell types indicating that TET3 is a crucial factor for cellular commitment and terminal differentiation 12 . In adult homeostasis, the role of Tet3 has been studied in a few tissues together with Tet2 , as both paralogs are ubiquitously expressed in most differentiated cells 4,13 .…”

Section: Introductionmentioning

confidence: 99%

TET3 regulates cellular terminal differentiation at the metabolic level

Mulet,

Grueso-Cortina,

Cortés-Cano

et al. 2024

Preprint

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TET-family members play an essential role in cell fate commitment and their dysfunctions result in arrested differentiation. TET3 is ubiquitously expressed in differentiated cells and essential in postnatal development due to yet unknown reasons. To define TET3 function in cell differentiation, we profiled the intestinal epithelium at the single-cell level from wild-type and Tet3 knockout mice. Here we show that, in the absence of TET3, enterocytes exhibit an aberrant differentiation trajectory and do not acquire a physiological cell identity due to an impairment in oxidative phosphorylation, specifically due to an ATP synthase assembly deficiency. Furthermore, our analysis demonstrates that the loss of TET3 compromises mitochondrial metabolic maturation and leads to a metabolic profile enriched in glycolysis-dependent anabolic pathways similar to those observed in undifferentiated cells. Collectively, our study has revealed the molecular mechanism by which TET3 regulates terminal differentiation at the metabolic level.

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Targeted erasure of DNA methylation by TET3 drives adipogenic reprogramming and differentiation

Cited by 17 publications

References 73 publications

WGBS of Differentiating Adipocytes Reveals Variations in DMRs and Context-Dependent Gene Expression

WGBS of Differentiating Adipocytes Reveals Variations in DMRs and Context-Dependent Gene Expression

Role of epigenetic regulatory mechanisms in age‐related bone homeostasis imbalance

TET3 regulates cellular terminal differentiation at the metabolic level

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