Dnmt3L Antagonizes DNA Methylation at Bivalent Promoters and Favors DNA Methylation at Gene Bodies in ESCs

Neri, Francesco; Krepelova, Anna; Incarnato, Danny; Maldotti, Mara; Parlato, Caterina; Galvagni, Federico; Matarese, Filomena; Stunnenberg, Hendrik G.; Oliviero, Salvatore

doi:10.1016/j.cell.2013.08.056

Cited by 155 publications

(142 citation statements)

References 59 publications

Supporting

Mentioning

125

Contrasting

Unclassified

Order By: Relevance

“…Dnmt1 and Dnmt3a expression was decreased in the Mafa KO islets (Fig. 3d), whereas Dnmt3l was upregulated, which may play a role in the maintenance of hypomethylation at promoters of bivalent developmental genes [36].…”

Section: Resultsmentioning

confidence: 99%

MafA is critical for maintenance of the mature beta cell phenotype in mice

2014

View full text Add to dashboard Cite

Aims/hypothesis The plasticity of adult somatic cells allows for their dedifferentiation or conversion to different cell types, although the relevance of this to disease remains elusive. Perturbation of beta cell identity leading to dedifferentiation may be implicated in the compromised functions of beta cells in diabetes, which is a current topic of islet research. This study aims to investigate whether or not v-Maf musculoaponeurotic fibrosarcoma oncogene family, protein A (MafA), a mature beta cell marker, is involved in maintaining mature beta cell phenotypes. Methods The fate and gene expression of beta cells were analysed in Mafa knockout (KO) mice and mouse models of diabetes in which the expression of MafA was reduced in the majority of beta cells. Results Loss of MafA reduced the beta to alpha cell ratio in pancreatic islets without elevating blood glucose to diabetic levels. Lineage tracing analyses showed reduced/lost expression of insulin in most beta cells, with a minority of the former beta cells converted to glucagon-expressing cells in Mafa KO mice. The upregulation of genes that are normally repressed in mature beta cells or transcription factors that are transiently expressed in endocrine progenitors was identified in Mafa KO islets as a hallmark of dedifferentiation. The compromised beta cells in db/db and multiple low-dose streptozotocin mice underwent similar dedifferentiation with expression of Mafb, which is expressed in immature beta cells. Conclusions/interpretation The maturation factor MafA is critical for the homeostasis of mature beta cells and regulates cell plasticity. The loss of MafA in beta cells leads to a deeper loss of cell identity, which is implicated in diabetes pathology.

show abstract

Section: Resultsmentioning

confidence: 99%

MafA is critical for maintenance of the mature beta cell phenotype in mice

2014

View full text Add to dashboard Cite

show abstract

“…Given that ADD 3l binding to the H3 N-terminus is disrupted by H3K4me3 (Ooi et al, 2007) (Figure 1C) and Dnmt3L incorporation stimulates Dnmt3a2 enzymatic activity (Gowher et al, 2005;Kareta et al, 2006), Dnmt3L itself may facilitate WT-, WWD-, R-Dnmt3a2 binding/activity to unmodified H3, limiting WWDDnmt3a2 access to H3K4 methylation. Dnmt3L has also been reported to exist in a complex with polycomb repressive complex 2 (PRC2) at bivalent promoters enriched with PRC2, H3K27me3, and H3K4me3 (Neri et al, 2013). This may further limit access of the WWDDnmt3a2 at these bivalent loci.…”

Section: Discussionmentioning

confidence: 99%

Engineering of a Histone-Recognition Domain in Dnmt3a Alters the Epigenetic Landscape and Phenotypic Features of Mouse ESCs

Noh¹,

Wang²,

Kim³

et al. 2018

Molecular Cell

View full text Add to dashboard Cite

“…Dnmt3l, a cofactor of Dnmt3a/3b, also rapidly decreases during ESC-EpiSC conversion and remains low in EpiSCs. A recent study have shown that DNMT3L interacts with PRC2, the polycomb complex that tri-methylates H3K27, which helps in maintaining the bivalent domains free of DNA methylation by preventing their access by DNMT3A/3B [56]. Although the total quantity of DNMT3A remains constant in EpiSCs and ESCs, an additional splicing isoform, DNMT3A1, is present in EpiSCs [51].…”

Section: Discussionmentioning

confidence: 99%

Stable Methylation at Promoters Distinguishes Epiblast Stem Cells from Embryonic Stem Cells and the In Vivo Epiblasts

Veillard

Marks

Bernardo

et al. 2014

Stem Cells and Development

View full text Add to dashboard Cite

Embryonic Stem Cells (ESCs) and Epiblast Stem Cells (EpiSCs) are the in vitro representatives of naïve and primed pluripotency, respectively. It is currently unclear how their epigenomes underpin the phenotypic and molecular characteristics of these distinct pluripotent states. Here, we performed a genome-wide comparison of DNA methylation between ESCs and EpiSCs by MethylCap-Seq. We observe that promoters are preferential targets for methylation in EpiSC compared to ESCs, in particular high CpG island promoters. This is in line with upregulation of the de novo methyltransferases Dnmt3a1 and Dnmt3b in EpiSC, and downregulation of the demethylases Tet1 and Tet2. Remarkably, the observed DNA methylation signature is specific to EpiSCs and differs from that of their in vivo counterpart, the postimplantation epiblast. Using a subset of promoters that are differentially methylated, we show that DNA methylation is established within a few days during in vitro outgrowth of the epiblast, and also occurs when ESCs are converted to EpiSCs in vitro. Once established, this methylation is stable, as ES-like cells obtained by in vitro reversion of EpiSCs display an epigenetic memory that only extensive passaging and sub-cloning are able to almost completely erase.

show abstract

Dnmt3L Antagonizes DNA Methylation at Bivalent Promoters and Favors DNA Methylation at Gene Bodies in ESCs

Cited by 155 publications

References 59 publications

MafA is critical for maintenance of the mature beta cell phenotype in mice

MafA is critical for maintenance of the mature beta cell phenotype in mice

Engineering of a Histone-Recognition Domain in Dnmt3a Alters the Epigenetic Landscape and Phenotypic Features of Mouse ESCs

Stable Methylation at Promoters Distinguishes Epiblast Stem Cells from Embryonic Stem Cells and the In Vivo Epiblasts

Contact Info

Product

Resources

About