Coordinated removal of repressive epigenetic modifications during induced reversal of cell identity

Tran, Khoa; Dillingham, Caleb M.; Sridharan, Rupa

doi:10.15252/embj.2019101681

Cited by 9 publications

(6 citation statements)

References 68 publications

(148 reference statements)

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“…Of note, the impact of TET1 on the success of iPSC formation is also modulated by the presence of AA ( Chen et al., 2013a ), raising the possibility that DNA demethylases might functionally interact with H3K9 methyltransferases and demethylases during enhanced reprogramming. Of note, Tet1 expression was linked to H3K9 demethylase activity during the conversion of partially into fully reprogrammed iPSCs ( Tran et al., 2019 ), supporting the interplay of DNA and histone methylation during reprogramming. It is noteworthy that our results strongly suggest that EHMT1 and EHMT2 have at least partially different roles during fibroblast reprogramming.…”

Section: Discussionmentioning

confidence: 86%

Context-Dependent Requirement of Euchromatic Histone Methyltransferase Activity during Reprogramming to Pluripotency

et al. 2020

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Summary Methylation of histone 3 at lysine 9 (H3K9) constitutes a roadblock for cellular reprogramming. Interference with methyltransferases or activation of demethylases by the cofactor ascorbic acid (AA) facilitates the derivation of induced pluripotent stem cells (iPSCs), but possible interactions between specific methyltransferases and AA treatment remain insufficiently explored. We show that chemical inhibition of the methyltransferases EHMT1 and EHMT2 counteracts iPSC formation in an enhanced reprogramming system in the presence of AA, an effect that is dependent on EHMT1. EHMT inhibition during enhanced reprogramming is associated with rapid loss of H3K9 dimethylation, inefficient downregulation of somatic genes, and failed mesenchymal-to-epithelial transition. Furthermore, transient EHMT inhibition during reprogramming yields iPSCs that fail to efficiently give rise to viable mice upon blastocyst injection. Our observations establish novel functions of H3K9 methyltransferases and suggest that a functional balance between AA-stimulated enzymes and EHMTs supports efficient and less error-prone iPSC reprogramming to pluripotency.

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Section: Discussionmentioning

confidence: 86%

Context-Dependent Requirement of Euchromatic Histone Methyltransferase Activity during Reprogramming to Pluripotency

et al. 2020

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“…Further evidence that DNA methylation protects against cell fate change comes from studies on the Ten-eleven translocation (TET) family proteins: TET1, TET2 and TET3 (Costa et al, 2013;Di Stefano et al, 2014;Doege et al, 2012;Hu et al, 2014;Sardina et al, 2018;Tran et al, 2019b). These proteins facilitate the removal of DNA methylation by oxidizing the methyl group of 5methylcytosine (Rasmussen and Helin, 2016;Tahiliani et al, 2009).…”

Section: Dna Methylationmentioning

confidence: 99%

Reprogramming: identifying the mechanisms that safeguard cell identity

2019

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Development and homeostasis rely upon concerted regulatory pathways to establish the specialized cell types needed for tissue function. Once a cell type is specified, the processes that restrict and maintain cell fate are equally important in ensuring tissue integrity. Over the past decade, several approaches to experimentally reprogram cell fate have emerged. Importantly, efforts to improve and understand these approaches have uncovered novel molecular determinants that reinforce lineage commitment and help resist cell fate changes. In this Review, we summarize recent studies that have provided insights into the various chromatin factors, post-transcriptional processes and features of genomic organization that safeguard cell identity in the context of reprogramming to pluripotency. We also highlight how these factors function in other experimental, physiological and pathological cell fate transitions, including direct lineage conversion, pluripotencyto-totipotency reversion and cancer.

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“…KDM5B is a major regulator of H3K4 methylation, 27 and several studies have shown that KDM3B demethylates the H3K9me2 in many tissues. 28,29 We therefore focused on KDM3B. The increase in KDM3B level and repression of H3K9me2 level was also observed in oocyte nuclei in vivo through immunofluorescence in ovaries of ovulation-induced F1 female offspring 30 (Figure 4E).…”

Section: Histone Demethylase Kdm3b Reduces H3k9me2 Modification Leadi...mentioning

confidence: 94%

Prenatal Lipopolysaccharides Exposure Induces Transgenerational Inheritance of Hypertension

Cao

Chen

et al. 2022

Circulation

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BACKGROUND: Adverse environmental exposure during the prenatal period can lead to diseases in the offspring, including hypertension. Whether or not the hypertensive phenotype can be transgenerationally transmitted is not known. METHODS: Pregnant Sprague Dawley rats were intraperitoneally injected with lipopolysaccharide (LPS) on gestation days 6, 8, 10, and 12 to generate the prenatal LPS exposure model. Blood pressure was monitored by both telemetry and tail-cuff method. RNA sequencing was performed to analyze transcriptome alteration in the kidney of the third generation. Tempol and spironolactone were used to test the potential prevention and therapeutic effect of targeting reactive oxygen species and mineralocorticoid receptor signaling, respectively. Molecular biological experiments were performed to illustrate the mechanism of epigenetic and transcription regulation. RESULTS: Prenatal LPS exposure can impair the ability to excrete a salt load and induce hypertension from the first to the third generations, with the fourth and fifth generations, inducing salt-sensitive hypertension. Compared with control pups, the transcriptome in the kidney of the hypertensive third-generation prenatal LPS–exposed offspring have upregulation of the Ras-related C3 botulinum toxin substrate 1 ( Rac1 ) gene and activation of mineralocorticoid receptor signaling. Furthermore, we found that LPS exposure during pregnancy triggered oxidative stress that upregulated KDM3B (histone lysine demethylase 3B) in the oocytes of first-generation female rats, leading to an inheritable low level of H3K9me2 (histone H3 lysine 9 dimethylation), resulting in the transgenerational upregulation of Rac1 . Based on these findings, we treated the LPS-exposed pregnant rats with the reactive oxygen species scavenger, tempol, which successfully prevented hypertension in the first-generation offspring and the transgenerational inheritance of hypertension. CONCLUSIONS: These findings show that adverse prenatal exposure induces transgenerational hypertension through an epigenetic-regulated mechanism and identify potentially preventive and therapeutic strategies for hypertension.

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Coordinated removal of repressive epigenetic modifications during induced reversal of cell identity

Cited by 9 publications

References 68 publications

Context-Dependent Requirement of Euchromatic Histone Methyltransferase Activity during Reprogramming to Pluripotency

Context-Dependent Requirement of Euchromatic Histone Methyltransferase Activity during Reprogramming to Pluripotency

Reprogramming: identifying the mechanisms that safeguard cell identity

Prenatal Lipopolysaccharides Exposure Induces Transgenerational Inheritance of Hypertension

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