Role of DNMTs in the Brain

Yildiz, Can Bora; Zimmer-Bensch, Geraldine

doi:10.1007/978-3-031-11454-0_15

Cited by 9 publications

(5 citation statements)

References 286 publications

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“…The results presented in this study can be potentially relevant to a wide range of pathologies where epigenetic mechanisms are of particular importance, such as cancer [ 52 , 53 ], allergies [ 54 ] , and neurodegenerative diseases [ 55 , 56 ]. In cancer, specific methylation and other alterations of the NFE2L2 promoter have been documented [ 12 , 57 , 58 ], which can alter the expression levels of NRF2, linked to carcinogenesis through metabolic reprogramming, tumor promotion, inflammation, and resistance to therapy.…”

Section: Discussionmentioning

confidence: 99%

The Transcription Factor NRF2 Has Epigenetic Regulatory Functions Modulating HDACs, DNMTs, and miRNA Biogenesis

et al. 2023

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The epigenetic regulation of gene expression is a complex and tightly regulated process that defines cellular identity and is associated with health and disease processes. Oxidative stress is capable of inducing epigenetic modifications. The transcription factor NRF2 (nuclear factor erythroid-derived 2-like 2) is a master regulator of cellular homeostasis, regulating genes bearing antioxidant response elements (AREs) in their promoters. Here, we report the identification of ARE sequences in the promoter regions of genes encoding several epigenetic regulatory factors, such as histone deacetylases (HDACs), DNA methyltransferases (DNMTs), and proteins involved in microRNA biogenesis. In this research, we study this possibility by integrating bioinformatic, genetic, pharmacological, and molecular approaches. We found ARE sequences in the promoter regions of genes encoding several HDACs, DNMTs, and proteins involved in miRNA biogenesis. We confirmed that NRF2 regulates the production of these genes by studying NRF2-deficient cells and cells treated with dimethyl fumarate (DMF), an inducer of the NRF2 signaling pathway. In addition, we found that NRF2 could be involved in the target RNA-dependent microRNA degradation (TDMD) of miR-155-5p through its interaction with Nfe2l2 mRNA. Our data indicate that NRF2 has an epigenetic regulatory function, complementing its traditional function and expanding the regulatory dimensions that should be considered when developing NRF2-centered therapeutic strategies.

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Section: Discussionmentioning

confidence: 99%

The Transcription Factor NRF2 Has Epigenetic Regulatory Functions Modulating HDACs, DNMTs, and miRNA Biogenesis

et al. 2023

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“…The DNA methylation landscape has been shown to vary dynamically depending on the cell type and developmental stage, and to respond to external signals (Guo et al, 2011; 2014; Skvortsova et al, 2019). DNMT1 function and DNA methylation regulate a broad spectrum of physiological processes, including the migration of neurons (Yildiz & Zimmer-Bensch, 2022) and glioma cells (Hua et al, 2018; Sun et al, 2017). However, whether and how DNMT targets specific gene loci, and induces transcriptionally relevant changes in DNA methylation signatures that elicit physiological responses, is not fully understood.…”

Section: Introductionmentioning

confidence: 99%

EphrinA5 regulates cell motility by modulating the targeting of DNMT1 to theNcam1promoter via lncRNA/DNA triplex formation

Yildiz

Kundu

Gehrmann

et al. 2023

Preprint

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Cell-cell communication is mediated by membrane receptors and their cognate ligands, such as the Eph/ephrin system, and dictates physiological processes, including cell proliferation and migration. However, whether and how Eph/ephrin signaling culminates in transcriptional regulation is largely unknown. Epigenetic mechanisms are key for integrating external signals, e.g., from neighboring cells, into the transcriptome. We have previously reported that ephrinA5 stimulation of immortalized cerebellar granule (CB) cells elicits transcriptional changes of lncRNAs and protein-coding genes. LncRNAs represent important adaptors for epigenetic writers through which they regulate gene expression. Here, we investigate the interaction of lncRNA with protein-coding genes by the combined power of in silico modeling of RNA/DNA interactions and respective wet lab approaches, in the context of ephrinA5-dependent regulation of cellular motility. We found that Snhg15, a cancer-related lncRNA, forms a triplex structure with the Ncam1 promoter and interacts with DNMT1. EphrinA5 stimulation leads to reduced Snhg15 expression, diminished Snhg15/DNMT1 interaction and decreased DNMT1 association with the Ncam1 promoter. These findings can explain the attenuated Ncam1 promoter methylation and elevated Ncam1 expression that in turn elicits decreased cell motility of CB cells. Hence, we propose that ephrinA5 influences gene transcription via lncRNA-targeted DNA methylation underlying the regulation of cellular motility.

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“…The DNA methylation landscape has been shown to vary dynamically depending on the cell type and developmental stage, and to respond to external signals [28][29][30]. DNMT1 function and DNA methylation regulate a broad spectrum of physiological processes, including the migration of neurons [31] and glioma cells [32,33]. However, whether and how DNMT targets speci c gene loci, and induces transcriptionally relevant changes in DNA methylation signatures that elicit physiological responses, is not fully understood.…”

Section: Introductionmentioning

confidence: 99%

EphrinA5 regulates cell motility by modulating lncRNA/DNA triplex-dependent targeting of DNMT1 to the Ncam1 promoter

Yildiz

Kundu

Gehrmann

et al. 2023

Preprint

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Background: Cell-cell communication is mediated by membrane receptors and their cognate ligands, such as the Eph/ephrin system, and dictates physiological processes, including cell proliferation and migration. However, whether and how Eph/ephrin signaling culminates in transcriptional regulation is largely unknown. Epigenetic mechanisms are key for integrating external “signals”, e.g., from neighboring cells, into the transcriptome. We have previously reported that ephrinA5 stimulation of immortalized cerebellar granule (CB) cells elicits transcriptional changes of lncRNAs and protein-coding genes. LncRNAs represent important adaptors for epigenetic writers through which they regulate gene expression. Hence, we here aimed to investigate, whether ephrinA5 can act on gene transcription through modulating lncRNA-mediated targeting of the DNA methyltransferase 1 (DNMT1) to gene promoters, thereby regulating cell motility. Results: We analyzed the interaction of lncRNA with protein-coding genes by the combined power of in silico modeling of RNA/DNA interactions and respective wet lab approaches. We found that Snhg15, a cancer-related lncRNA, forms a triplex structure with the Ncam1 promoter and interacts with DNMT1. EphrinA5 stimulation leads to reduced Snhg15 expression, diminished Snhg15/DNMT1 interaction and decreased DNMT1 association with the Ncam1 promoter. These findings can explain the attenuated Ncam1 promoter methylation and elevated Ncam1 expression induced by ephrinA5 stimulation that in turn elicits decreased cell motility of CB cells. Conclusion: Based on our findings, we propose that ephrinA5 influences gene transcription via lncRNA-targeted DNA methylation underlying the regulation of cellular motility. Such mechanism could be relevant in the context of cancerogenic processes, known to involve Eph/ephrin signaling and epigenetic remodelling.

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Role of DNMTs in the Brain

Cited by 9 publications

References 286 publications

The Transcription Factor NRF2 Has Epigenetic Regulatory Functions Modulating HDACs, DNMTs, and miRNA Biogenesis

The Transcription Factor NRF2 Has Epigenetic Regulatory Functions Modulating HDACs, DNMTs, and miRNA Biogenesis

EphrinA5 regulates cell motility by modulating the targeting of DNMT1 to theNcam1promoter via lncRNA/DNA triplex formation

EphrinA5 regulates cell motility by modulating lncRNA/DNA triplex-dependent targeting of DNMT1 to the Ncam1 promoter

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