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

Meng Wu; Siwu Peng; Jialiang Yang; Zhidong Tu; Xiaoqiang Cai; Chen-Leng Cai; Zhong Wang; Yong Zhao

doi:10.1038/cr.2014.113

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

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

Authors

Meng Wu¹, Siwu Peng¹, Jialiang Yang², Zhidong Tu², Xiaoqiang Cai³, Chen-Leng Cai³, Zhong Wang⁴, Yong Zhao¹

Affiliations

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.

MeSH terms

Animals
Antineoplastic Agents, Hormonal / pharmacology
Chromatin Immunoprecipitation
Cluster Analysis
DNA-Binding Proteins / deficiency
DNA-Binding Proteins / genetics
DNA-Binding Proteins / metabolism*
Epigenesis, Genetic*
GATA4 Transcription Factor / metabolism
HEK293 Cells
Histone Deacetylases / metabolism
Homeobox Protein Nkx-2.5
Homeodomain Proteins / metabolism*
Humans
Mice
Mice, Inbred C57BL
Mice, Knockout
Muscle Contraction / drug effects
Myocytes, Cardiac / drug effects
Myocytes, Cardiac / metabolism*
Nuclear Proteins / deficiency
Nuclear Proteins / genetics
Nuclear Proteins / metabolism*
Sinoatrial Node / metabolism*
T-Box Domain Proteins / deficiency
T-Box Domain Proteins / genetics
T-Box Domain Proteins / metabolism
Tamoxifen / pharmacology
Transcription Factors / metabolism*

Substances

Antineoplastic Agents, Hormonal
Arid1a protein, mouse
DNA-Binding Proteins
GATA4 Transcription Factor
Gata4 protein, mouse
Homeobox Protein Nkx-2.5
Homeodomain Proteins
Nkx2-5 protein, mouse
Nuclear Proteins
T-Box Domain Proteins
T-box transcription factor 5
Tbx3 protein, mouse
Transcription Factors
Tamoxifen
Histone Deacetylases
histone deacetylase 3

Abstract

MeSH terms

Substances

Grants and funding