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Related Experiment Video

Updated: Dec 6, 2025

Generation of Murine Cardiac Pacemaker Cell Aggregates Based on ES-Cell-Programming in Combination with Myh6-Promoter-Selection
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ATAC-Seq Reveals an Isl1 Enhancer That Regulates Sinoatrial Node Development and Function.

Giselle Galang1, Ravi Mandla1, Hongmei Ruan1

  • 1Cardiology Division (G.G., R.M., H.R., C.J., R.S.W., P.K.R.A., A.R., M.B.S., V.V.), University of California, San Francisco.

Circulation Research
|October 12, 2020
PubMed
Summary

Scientists identified novel regulatory elements controlling heart pacemaker cell function. A specific enhancer near the Isl1 gene is crucial for heart rhythm and may influence human heart rate, offering new insights into cardiac development and arrhythmias.

Keywords:
chromatinheart ratemicesinoatrial nodezebrafish

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Area of Science:

  • Cardiovascular Biology
  • Epigenetics
  • Genomics

Background:

  • Cardiac pacemaker cells (PCs) in the sinoatrial node (SAN) possess a unique gene expression profile enabling automaticity and heartbeat initiation.
  • Key transcription factors like Isl1, Tbx3, and Shox2 are known regulators in SAN, but the underlying cis-regulatory architecture remains largely undefined.
  • Specific enhancers governing PC-specific gene expression and SAN development have not been previously identified.

Purpose of the Study:

  • To delineate the epigenetic landscape of cardiac pacemaker cells (PCs) using comparative ATAC-seq (assay for transposase-accessible chromatin with sequencing).
  • To discover novel enhancers critical for SAN gene regulation, cardiac development, and overall function.
  • To investigate the role of identified enhancers in PC development and heart rhythm.

Main Methods:

  • Performed ATAC-seq on sorted neonatal mouse SAN to compare accessible chromatin regions between PCs and right atrial cardiomyocytes.
  • Identified PC-enriched ATAC-seq peaks as candidate SAN regulatory elements, analyzing proximity to known SAN genes and transcription factor binding sites.
  • Experimentally validated novel SAN enhancers using transgenic mouse models, including deletion of a specific enhancer at the Isl1 locus.

Main Results:

  • Discovered distinct accessible chromatin regions in PCs, correlating with their gene expression profile and harboring novel SAN enhancers.
  • Identified a 2.9-kb regulatory element at the Isl1 locus, active in the cardiac inflow early in development and throughout SAN maturation.
  • Demonstrated that deletion of this Isl1 enhancer leads to SAN hypoplasia and sinus arrhythmias in mice, with conserved function in zebrafish and potential relevance to human heart rate regulation.

Conclusions:

  • Cardiac pacemaker cells exhibit unique accessible chromatin regions containing novel SAN enhancers that are crucial for their function.
  • A conserved SAN enhancer at the Isl1 locus plays a vital role in PC development and SAN function, regulating cis-regulation of Isl1.
  • The identified human ISL1 enhancer region may similarly influence human SAN function and heart rate, suggesting evolutionary conservation.