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Identification of genes regulated by REST in developing hearts

ABSTRACT: Selective suppression of cardiac gene expression by RE-1 silencing transcription factor (REST) in embryonic stage is essential for cardiogenesis and function; however, the underlying mechanism remains unclear. In this study, we show that REST suppression of cardiac genes during development is temporarily regulated through non-CpG methylation at REST binding sites. Gene expression analyses revealed that the expression of Hcn2 (hyperpolarization-activated cyclic nucleotide-gated ion channel 2), a REST-targeted gene, was developmentally upregulated, while DNMT3B level and REST expression was downregulated. Concurrently, bisulﬁte sequencing and chromatin immunoprecipitation (ChIP) analyses showed that non-CpG methylation of the REST site located in the Hcn2 intron 1 and its co-occupancy by REST and DNMT3B were diminished at E?. Further in vitro inhibition and in vivo myocardial deletion of Rest and Dnmt3b uncovered that non-CpG methylation of the REST site by DNMT3B promoted REST binding to suppress Hcn2 transcription in the embryonic stage. Moreover, using an integrated approach of transcriptomic analysis, ChIP assay, and bisulfate sequencing, we showed that the same mechanism regulated the expression of ~30% REST targeted genes. The expression of these genes was developmentally upregulated as Hcn2. Together, our results suggest that non-CpG methylation at a subset of transcription factor binding sites may regulate cardiac gene program critical for heart development and its dysregulation may contribute to heart disease.

ORGANISM(S): Mus musculus

PROVIDER: GSE80378 | GEO | 2017/02/13

SECONDARY ACCESSION(S): PRJNA318773

REPOSITORIES: GEO

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