DNMT3A and TET1 cooperate to regulate promoter epigenetic landscapes in mouse embryonic stem cells

Gu, Tianpeng; Lin, Xueqiu; Cullen, Shay; Luo, Min; Jeong, Mira; Estécio, Marcos R.H.; Shen, Jianjun; Hardikar, Swanand; Sun, Deqiang; Su, Jianzhong; Rux, Danielle; Guzman, Anna; Lee, Minjung; Qi, Lei; Chen, Jiajia; Kyba, Michael; Huang, Yun; Chen, Taiping; Li, Wei; Goodell, Margaret A.

doi:10.1186/s13059-018-1464-7

Cited by 143 publications

(131 citation statements)

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“…Previous reports have also shown TET1 and DNMT3A have competitive binding to regulate promoters in mouse embryonic stem cells 83 . In addition, in honey bee Dnmts and Tet (homolog of vertebrate DNMTs and TETs) were found to target memory-associated genes sequentially, while Dnmt3 was found in a negative feedback loop for DNA methylation 84 .…”

Section: Regulatory Loops On Dna Methylationmentioning

confidence: 83%

Identification of DNA motifs that regulate DNA methylation

Wang¹,

Zhang²,

Ngo³

et al. 2019

Preprint

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DNA methylation is an important epigenetic mark but how its locus-specificity is decided in relation to DNA sequence is not fully understood. Here, we have analyzed 34 diverse wholegenome bisulfite sequencing datasets in human and identified 313 motifs, including 92 and 221 associated with methylation (methylation motifs, MMs) and unmethylation (unmethylation motifs, UMs), respectively. The functionality of these motifs is supported by multiple lines of evidences. First, the methylation levels at the MM and UM motifs are respectively higher and lower than the genomic background. Second, these motifs are enriched at the binding sites of methylation modifying enzymes including DNMT3A and TET1, indicating their possible roles of recruiting these enzymes. Third, these motifs significantly overlap with SNPs associated with gene expression and those with DNA methylation. Fourth, disruption of these motifs by SNPs is associated with significantly altered methylation level of the CpGs in the neighbor regions. Furthermore, these motifs together with somatic SNPs are predictive of cancer subtypes and patient survival. We revealed some of these motifs were also associated with histone modifications, suggesting possible interplay between the two types of epigenetic modifications. We also found some motifs form feed forward loops to contribute to DNA methylation dynamics. Results Defining DNA methylation regions and de novo motif discoveryWe aimed to identify DNA motifs associated with DNA methylation and thus started with searching for methylation regions that have the strongest signals. We collected whole genome bisulfite sequencing (WGBS) data of 34 human methylomes generated by the NIH Roadmap Epigenomics Project 15,16 (Figure 1A). We took an approach similar to the Ziller et al. study 17 and defined 1.55 million methylation regions containing 11.5 million CpG sites in the 34 methylomes. Because the methylome data is noisy, we only considered regions containing 2 or more CpGs within 400 bp apart, which covers 29.2% of the human genome.

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Section: Regulatory Loops On Dna Methylationmentioning

confidence: 83%

Identification of DNA motifs that regulate DNA methylation

Wang¹,

Zhang²,

Ngo³

et al. 2019

Preprint

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“…Our study showed that temperature stress had no effect on the expression of Tet2 and Tet3. On the other hand, Tet1 was upregulated at 41 C compared to 37 C. We found that both Tet1 and Dnmt3a were highly expressed at 41 C. A recent study reported that DNMT3a and TET1 regulate gene expression not only by controlling DNA methylation but also regulating the histone landscape upon binding to the relevant promoters [38].…”

Section: Discussionmentioning

confidence: 52%

Cross-talk between energy metabolism and epigenetics during temperature stress response in C2C12 myoblasts

Sajjanar

Siengdee

Trakooljul

et al. 2019

International Journal of Hyperthermia

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Objective: Environmental stress induces disturbances in cell energy metabolism and may cause epigenetic modifications. This study aimed to understand the possible impact of temperature stress (35 C, 39 C and 41 C, compared to control 37 C) on energy metabolism and epigenetic modifications, such as DNA methylation and histone H4 acetylation, as well as its effects on the expression of genes responsible for epigenetic changes, in mouse skeletal myoblasts (C2C12 cells). Methods: The results showed significantly reduced maximal respiration and spare respiratory capacity under heat stress (39 C and 41 C), suggesting that mitochondrial functions were compromised under these conditions. The glycolytic capacity and glycolysis markedly increased following low-temperature stress (35 C). The results suggested that, under cold stress, cells prefer glycolysis as a rapid compensatory mechanism to meet energy requirements for adaptive thermogenic response. Results: Epigenetic changes (histone H4 acetylation and global DNA methylation) were observed under both heat and cold stress. Among the genes coding for DNA methyltransferases, the Dnmt3a was significantly increased under high-temperature conditions (39 C and 41 C), while Dnmt1 expression was significantly increased at low temperature (35 C), indicating that under these conditions the cells preferred maintenance of methylation to de novo methylation activity. An expression pattern similar to Dnmt3a was observed for Gcn5, encoding for a histone acetyltransferase. The study revealed that temperature stress induced changes in the metabolic profiles, as well as epigenetic modifications, including the dynamics of the key enzymes. Conclusion: The results indicated the existence of crosstalk mechanisms between energy metabolism and epigenetics during cell stress response. ARTICLE HISTORY

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Section: Epigenome States During Islet Lineage Progressionmentioning

confidence: 99%

“…We also identify 1,918 genes that show differential isoform use across stage transitions (Figures S3H and S3I; Table S2). These include a switch towards DNMT3A and TET1 isoforms generated from alternative promoters upon endocrine commitment ( Figures 1C, S3J and S3K), which reportedly confer distinct subnuclear localization/biochemical activities (Chen et al, 2002;Gu et al, 2018; Zhang et al, 2016).We next used ChIP-seq to profile H3K27ac, which marks active promoters/enhancers, and H3K4me1, which marks either active or poised promoters/enhancers (see below) (Creyghton et al, 2010;Heintzman et al, 2009;Rada-Iglesias et al, 2011), and identified 361,576 sites enriched for H3K27ac/H3K4me1 in at least one stage. Despite consistent genomic coverage and histone modification levels during differentiation ( Figure S2A, S4A-S4C), >75% of H3K27ac/ H3K4me1 regions are detected in at most 3 stages ( Figure S4D).…”

mentioning

confidence: 99%

Dissecting mechanisms of human islet differentiation and maturation through epigenome profiling

Alvarez-Dominguez

Donaghey

Jhr

et al. 2019

Preprint

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Investigating pancreatic islet differentiation from human stem cells in vitro provides a unique opportunity to dissect mechanisms that operate during human development in utero. We developed methods to profile DNA methylation, chromatin accessibility, and histone modifications from pluripotent stem cells to mature pancreatic islet cells, uncovering widespread epigenome remodeling upon endocrine commitment. Key lineage-defining loci are epigenetically primed before activation, foreshadowing cell fate commitment, and we show that priming of αcell-specific enhancers steers polyhormonal cells toward an α-cell fate. We further dissect pioneer factors and core regulatory circuits across islet cell differentiation and maturation stages, which identify LMX1B as a key regulator of in vitro-derived endocrine progenitors. Finally, by contrasting maturing stem cell-derived to natural β-cells, we discover that circadian metabolic cycles trigger rhythmic control of insulin synthesis and release and promote mature insulin responsiveness via an increased glucose threshold. These findings form a basis for understanding mechanisms orchestrating human islet cell specification and maturation. 4 domains, putative pioneer factors that establish them, and their state dynamics throughout human islet development. We find that endocrine specification involves widespread enhancer resetting and is foreshadowed by the priming of lineage-specifying loci. Accordingly, we show that priming of α-cell-specific enhancers in PH cells precedes resolution toward an α-cell fate. We further infer core regulatory circuits for each islet differentiation stage, capturing both known and unexpected factors including LMX1B, which we validate as key for in vitro-derived endocrine progenitors. Finally, we contrast regulatory landscapes in SC-β with their natural counterparts to uncover a role for circadian rhythms in fostering mature insulin responsiveness.Metabolically synchronized cadaveric/SC-islets gain cyclic transcription of genes controlling insulin synthesis/release and rhythmic insulin responses with an increased glucose threshold, a hallmark of functional maturity. These data form a basis for understanding genetic and epigenetic mechanisms controlling human islet cell fate and function. RESULTS In vitro isolation of human islet developmental intermediatesWe used the directed differentiation of human pluripotent stem cells (hPSC) into functional islet cells as a model to study human islet development (Figures 1A and S1A). Based on marker genes, we used flow cytometry to isolate cells at defined differentiation stages representing key intermediates during islet lineage progression (Figures S1B and S1C): undifferentiated hPSC, SOX17 + definitive endoderm (DE) cells, PDX1 + early pancreatic progenitors (PP1), PDX1 + NKX6.1 + late progenitors (PP2), NGN3 + endocrine 5 progenitors (EN), and monohormonal (INS + GCG -) SC-β as well as polyhormonal (INS + GCG + )PH cells. To isolate live SC-β and PH, we developed a strategy that combines endocrine cell enric...

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DNMT3A and TET1 cooperate to regulate promoter epigenetic landscapes in mouse embryonic stem cells

Cited by 143 publications

References 54 publications

Identification of DNA motifs that regulate DNA methylation

Identification of DNA motifs that regulate DNA methylation

Cross-talk between energy metabolism and epigenetics during temperature stress response in C2C12 myoblasts

Dissecting mechanisms of human islet differentiation and maturation through epigenome profiling

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