title: Baf250a orchestrates an epigenetic pathway to repress the Nkx2.5-directed contractile cardiomyocyte program in the sinoatrial node.
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.
authors.affiliation: 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.
authors.forename: Meng
authors.initials: M
authors.lastname: Wu
authors.affiliation: 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.
authors.forename: Siwu
authors.initials: S
authors.lastname: Peng
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA.
authors.forename: Jialiang
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA.
authors.forename: Zhidong
authors.initials: Z
authors.lastname: Tu
authors.affiliation: 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.
authors.forename: Xiaoqiang
authors.initials: X
authors.lastname: Cai
authors.affiliation: 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.
authors.forename: Chen-Leng
authors.initials: CL
authors.lastname: Cai
authors.affiliation: Department of Cardiac Surgery, Cardiovascular Research Center, University of Michigan, 2800 Plymouth Road, Ann Arbor, MI 48109, USA.
authors.forename: Zhong
authors.initials: Z
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhao
mesh_terms: D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D047369:Chromatin Immunoprecipitation; D016000:Cluster Analysis; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D044127:Epigenesis, Genetic; D050991:GATA4 Transcription Factor / Q000378:metabolism; D057809:HEK293 Cells; D006655:Histone Deacetylases / Q000378:metabolism; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009119:Muscle Contraction / Q000187:drug effects; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism*; D009687:Nuclear Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D012849:Sinoatrial Node / Q000378:metabolism*; D020825:T-Box Domain Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D013629:Tamoxifen / Q000494:pharmacology; D014157:Transcription Factors / Q000378:metabolism*; D000099186:Histone Deacetylase 3
chemical_list: D018931:Antineoplastic Agents, Hormonal; D004268:DNA-Binding Proteins; D050991:GATA4 Transcription Factor; D006655:Histone Deacetylases; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins; D009687:Nuclear Proteins; D020825:T-Box Domain Proteins; D013629:Tamoxifen; D014157:Transcription Factors; D000099186:Histone Deacetylase 3; C511511:Arid1a protein, mouse; C484171:Gata4 protein, mouse; C484469:Nkx2-5 protein, mouse; C103172:T-box transcription factor 5; C491460:Tbx3 protein, mouse