Role of NRSF/REST in the Regulation of Cardiac Gene Expression and Function

Kuwahara, Koichiro

doi:10.1253/circj.cj-13-1210

Cited by 27 publications

(17 citation statements)

References 35 publications

(33 reference statements)

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“…A). Many of these interaction nodes are associated with adverse health phenotypes: CUX1 repairs DNA oxidative damage and is a tumour suppressor , REL and NFKB2 are part of the NFKB signalling pathway and associated with immune function and cancer ; REST is a transcriptional repressor linked with prostate cancer and regulates cardiac gene expression ; EP300 is a transcriptional co‐activator that regulates circadian gene expression and ESR1‐stimulated expression and is linked with prostate cancer ; IL6, and MAPK11 are linked with immune function and cancer ; PIK3CA and PIK3R1 are linked with insulin resistance, immune response and cancer , PPARA is associated with lipid homeostasis, inflammation, and type‐2 diabetes , MLL is a methyltransferase that regulates circadian gene expression and is linked with cancer , and ESR1 regulates gene expression and is associated with cancer . An overlapping set of interacting genes are affected by both sleep restriction and mistimed sleep: MLL, CSNK1ε, MAP kinase transcripts (MAPK11, MAPK12, MAPK13), HSPA5, REST, NCOR1, IL6, MED1, and RORA.…”

Section: Congruency Of Human and Mouse Rhythmic Gene Expression Signalsmentioning

confidence: 99%

Exploiting human and mouse transcriptomic data: Identification of circadian genes and pathways influencing health

et al. 2015

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The power of the application of bioinformatics across multiple publicly available transcriptomic data sets was explored. Using 19 human and mouse circadian transcriptomic data sets, we found that NR1D1 and NR1D2 which encode heme‐responsive nuclear receptors are the most rhythmic transcripts across sleep conditions and tissues suggesting that they are at the core of circadian rhythm generation. Analyzes of human transcriptomic data show that a core set of transcripts related to processes including immune function, glucocorticoid signalling, and lipid metabolism is rhythmically expressed independently of the sleep‐wake cycle. We also identify key transcripts associated with transcription and translation that are disrupted by sleep manipulations, and through network analysis identify putative mechanisms underlying the adverse health outcomes associated with sleep disruption, such as diabetes and cancer. Comparative bioinformatics applied to existing and future data sets will be a powerful tool for the identification of core circadian‐ and sleep‐dependent molecules.

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Section: Congruency Of Human and Mouse Rhythmic Gene Expression Signalsmentioning

confidence: 99%

Exploiting human and mouse transcriptomic data: Identification of circadian genes and pathways influencing health

et al. 2015

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“…Repressor element 1 (RE1)-silencing transcription factor (REST; also known as NRSF for Neuron Restrictive Silencer Factor) is known to suppress the expression of neuronal genes in non-neuronal cells (3,4), but its functions have been recently shown to be more diverse. In developing mouse hearts, REST represses the expression of a subset of cardiac genes, such as atrial natriuretic peptide ( Nppa ), brain natriuretic peptide ( Nppb ), and the pacemaker hyperpolarization-activated cyclic nucleotide-modulated potassium channel protein 2 ( Hcn2 ) (5,6). Developmentally regulated expression of Hcn2 , which encodes the prominent HCN isoform expressed in the adult ventricular cardiomyocytes, contributes to the maturation of cardiac pacemaker channels (7–9).…”

Section: Introductionmentioning

confidence: 99%

Non-CpG methylation by DNMT3B facilitates REST binding and gene silencing in developing mouse hearts

Zhang

Wang

et al. 2016

Nucleic Acids Research

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The dynamic interaction of DNA methylation and transcription factor binding in regulating spatiotemporal gene expression is essential for embryogenesis, but the underlying mechanisms remain understudied. In this study, using mouse models and integration of in vitro and in vivo genetic and epigenetic analyses, we show that the binding of REST (repressor element 1 (RE1) silencing transcription factor; also known as NRSF) to its cognate RE1 sequences is temporally regulated by non-CpG methylation. This process is dependent on DNA methyltransferase 3B (DNMT3B) and leads to suppression of adult cardiac genes in developing hearts. We demonstrate that DNMT3B preferentially mediates non-CpG methylation of REST-targeted genes in the developing heart. Downregulation of DNMT3B results in decreased non-CpG methylation of RE1 sequences, reduced REST occupancy, and consequently release of the transcription suppression during later cardiac development. Together, these findings reveal a critical gene silencing mechanism in developing mammalian hearts that is regulated by the dynamic interaction of DNMT3B-mediated non-CpG methylation and REST binding.

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“…Interestingly, REST has been shown to be involved in the maintenance of normal functions in adult heart. Indeed, studies on transcriptionnal regulation of cardiac genes during cardiac dysfunction and arrhythmogenesis revealed REST as an important regulator of fetal cardiac genes . Inhibition of REST in adult mice heart induces the expression of ANP and BNP which are necessary for proper cardiomyocytes function .…”

Section: Introductionmentioning

confidence: 99%

A Role for RE-1-Silencing Transcription Factor in Embryonic Stem Cells Cardiac Lineage Specification

et al. 2016

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During development, lineage specification is controlled by several signaling pathways involving various transcription factors (TFs). Here, we studied the RE-1-silencing transcription factor (REST) and identified an important role of this TF in cardiac differentiation. Using mouse embryonic stem cells (ESC) to model development, we found that REST knockout cells lost the ability to differentiate into the cardiac lineage. Detailed analysis of specific lineage markers expression showed selective downregulation of endoderm markers in REST-null cells, thus contributing to a loss of cardiogenic signals. REST regulates cardiac differentiation of ESCs by negatively regulating the Wnt/b-catenin signaling pathway and positively regulating the cardiogenic TF Gata4. We propose here a new role for REST in cell fate specification besides its well-known repressive role of neuronal differentiation. STEM CELLS 2016;34:860-872 SIGNIFICANCE STATEMENTREST has been implicated in fetal cardiac development and heart function, but its role has never been studied in embryonic stem cells cardiac differentiation. Here, we shed light on a novel function of REST. REST has primarily been associated with control of neuronal development where it serves to maintain neural progenitor cells by transcriptionally suppressing neuronal specifying genes. These new data show that REST also has a key role in cardiac lineage development of embryonic stem cells. We show that REST regulates Wnt signaling and activates Gata4 expression, thus establishing mechanistic connections between these key molecular players and their roles in cardiogenesis.

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Role of NRSF/REST in the Regulation of Cardiac Gene Expression and Function

Cited by 27 publications

References 35 publications

Exploiting human and mouse transcriptomic data: Identification of circadian genes and pathways influencing health

Exploiting human and mouse transcriptomic data: Identification of circadian genes and pathways influencing health

Non-CpG methylation by DNMT3B facilitates REST binding and gene silencing in developing mouse hearts

A Role for RE-1-Silencing Transcription Factor in Embryonic Stem Cells Cardiac Lineage Specification

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