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Nkx2.5-dependent alterations of the embryonic heart DNA methylome identify novel cis-regulatory elements in cardiac development

View ORCID ProfileBushra Gorsi, View ORCID ProfileTimothy L. Mosbruger, View ORCID ProfileMegan Smith, View ORCID ProfileJonathon T. Hill, View ORCID ProfileH. Joseph Yost
doi: https://doi.org/10.1101/186395
Bushra Gorsi
1Molecular Medicine Program, Eccles Institute of Human Genetics, University of Utah, 15 North 2030 East, University of Utah, Salt Lake City, Utah, USA 84112-5330
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Timothy L. Mosbruger
1Molecular Medicine Program, Eccles Institute of Human Genetics, University of Utah, 15 North 2030 East, University of Utah, Salt Lake City, Utah, USA 84112-5330
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Megan Smith
1Molecular Medicine Program, Eccles Institute of Human Genetics, University of Utah, 15 North 2030 East, University of Utah, Salt Lake City, Utah, USA 84112-5330
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Jonathon T. Hill
1Molecular Medicine Program, Eccles Institute of Human Genetics, University of Utah, 15 North 2030 East, University of Utah, Salt Lake City, Utah, USA 84112-5330
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H. Joseph Yost
1Molecular Medicine Program, Eccles Institute of Human Genetics, University of Utah, 15 North 2030 East, University of Utah, Salt Lake City, Utah, USA 84112-5330
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  • For correspondence: jyost@genetics.utah.edu
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Abstract

Transcription factor Nkx2.5 is frequently mutated in congenital heart disease, but the mechanisms by which Nkx2.5 regulates heart development are poorly understood. By generating comprehensive DNA methylome maps from zebrafish embryonic hearts in nxk2.5 mutants and siblings, we discovered that Nkx2.5 regulates DNA methylation patterns during cardiac morphogenesis. We identified hundreds of Nkx-dependent heart-specific Differentially Methylated Regions (nhDMRs). A majority of the nhDMRs were hypomethylated in nkx2.5−/- hearts, correlating with changes in the mutant transcriptome, suggesting Nkx2.5 functions largely as a repressor. Distinct Nkx DNA-binding motifs were significantly enriched in subclasses of nhDMRs. Furthermore, nhDMRs were significantly associated with histone H3K4me1 and H3K27ac post-translational modifications, suggesting Nkx2.5 regulates gene expression by differential methylation of cis-regulatory elements. Using transgenics, we validated several nhDMRs with enhancer activities in the heart. We propose a novel role of Nkx2.5 mediated DNA methylation is integral in activating and repressing Nkx2.5 target genes during heart development.

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Posted September 08, 2017.
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Nkx2.5-dependent alterations of the embryonic heart DNA methylome identify novel cis-regulatory elements in cardiac development
Bushra Gorsi, Timothy L. Mosbruger, Megan Smith, Jonathon T. Hill, H. Joseph Yost
bioRxiv 186395; doi: https://doi.org/10.1101/186395
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Nkx2.5-dependent alterations of the embryonic heart DNA methylome identify novel cis-regulatory elements in cardiac development
Bushra Gorsi, Timothy L. Mosbruger, Megan Smith, Jonathon T. Hill, H. Joseph Yost
bioRxiv 186395; doi: https://doi.org/10.1101/186395

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