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Cell Res. 2014 Oct;24(10):1201-13. doi: 10.1038/cr.2014.113. Epub 2014 Aug 22.

Baf250a orchestrates an epigenetic pathway to repress the Nkx2.5-directed contractile cardiomyocyte program in the sinoatrial node.

Author information

1
1] Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA [2] Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA.
2
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA.
3
1] Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA [2] Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA.
4
Department of Cardiac Surgery, Cardiovascular Research Center, University of Michigan, 2800 Plymouth Road, Ann Arbor, MI 48109, USA.

Abstract

The sinoatrial node (SAN) is essential for rhythmic beating of the heart; however, our understanding of what controls proper functioning of the SAN remains primitive. To explore molecular control of SAN function, we specifically deleted Baf250a, a key regulatory component of the ATP-dependent chromatin remodeling complex SWI/SNF, in the SAN. Deletion of Baf250a in the SAN led to sinus bradycardia. Time series analysis of dysregulated genes after deletion of Baf250a reveals a transcriptional hierarchy maintaining pacemaker cell identity, i.e., Baf250a activates the expression of Tbx3, and Baf250a, Tbx3 and histone deacetylase 3 coordinately repress the expression of Nkx2.5. Disruption of this repressive pathway switches on expression of Nkx2.5, which stimulates expression of Gata4 and Tbx5. These three cardiac transcription factors further turn on a contractile cardiomyocyte program in the SAN, which eventually leads to sick sinus disease (SSD). Our study suggests that disruption of key genetic pathways regulating cardiac lineage segregation may cause SSD and cardiac arrhythmias in general.

PMID:
25145359
PMCID:
PMC4185344
DOI:
10.1038/cr.2014.113
[Indexed for MEDLINE]
Free PMC Article

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