PUBLICATION
ATAC-seq Reveals an Isl1 Enhancer that Regulates Sinoatrial Node Development and Function
- Authors
- Galang, G., Mandla, R., Ruan, H., Jung, C., Sinha, T., Stone, N.R., Wu, R.S., Mannion, B.J., Allu, P.K., Chang, K., Rammohan, A., Shi, M.B., Pennacchio, L.A., Black, B.L., Vedantham, V.
- ID
- ZDB-PUB-201015-5
- Date
- 2020
- Source
- Circulation research 127(12): 1502-1518 (Journal)
- Registered Authors
- Black, Brian
- Keywords
- none
- MeSH Terms
-
- Action Potentials
- Animals
- Arrhythmia, Sinus/genetics
- Arrhythmia, Sinus/metabolism*
- Arrhythmia, Sinus/physiopathology
- Biological Clocks*
- Chromatin Immunoprecipitation Sequencing*
- Enhancer Elements, Genetic*
- Epigenesis, Genetic
- Female
- Gene Expression Regulation, Developmental
- Gestational Age
- Heart Rate*
- Humans
- LIM-Homeodomain Proteins/genetics
- LIM-Homeodomain Proteins/metabolism*
- Male
- Mice, Inbred C57BL
- Mice, Transgenic
- Polymorphism, Single Nucleotide
- Sinoatrial Node/metabolism*
- Sinoatrial Node/physiopathology
- Time Factors
- Transcription Factors/genetics
- Transcription Factors/metabolism*
- Zebrafish/genetics
- Zebrafish/metabolism
- PubMed
- 33044128 Full text @ Circ. Res.
Citation
Galang, G., Mandla, R., Ruan, H., Jung, C., Sinha, T., Stone, N.R., Wu, R.S., Mannion, B.J., Allu, P.K., Chang, K., Rammohan, A., Shi, M.B., Pennacchio, L.A., Black, B.L., Vedantham, V. (2020) ATAC-seq Reveals an Isl1 Enhancer that Regulates Sinoatrial Node Development and Function. Circulation research. 127(12):1502-1518.
Abstract
Rationale: Cardiac pacemaker cells (PCs) in the sinoatrial node (SAN) have a distinct gene expression program that allows them to fire automatically and initiate the heartbeat. Although critical SAN transcription factors, including Isl1, Tbx3, and Shox2, have been identified, the cis-regulatory architecture that governs PC-specific gene expression is not understood, and discrete enhancers required for gene regulation in the SAN have not been identified. Objective: To define the epigenetic profile of PCs using comparative ATAC-seq and to identify novel enhancers involved in SAN gene regulation, development and function. Methods and Results: We used ATAC-seq on sorted neonatal mouse SAN to compare regions of accessible chromatin in PCs and right atrial cardiomyocytes. PC-enriched ATAC-seq peaks, representing candidate SAN regulatory elements, were located near established SAN genes and were enriched for distinct sets of TF binding sites. Among several novel SAN enhancers that were experimentally validated using transgenic mice, we identified a 2.9-kb regulatory element at the Isl1 locus that was active specifically in the cardiac inflow at E8.5 and throughout later SAN development and maturation. Deletion of this enhancer from the genome of mice resulted in SAN hypoplasia and sinus arrhythmias. The mouse SAN enhancer also directed reporter activity to the inflow tract in developing zebrafish hearts, demonstrating deep conservation of its upstream regulatory network. Finally, single nucleotide polymorphisms in the human genome that occur near the region syntenic to the mouse enhancer exhibit significant associations with resting heart rate in human populations. Conclusions: (1) PCs have distinct regions of accessible chromatin that correlate with their gene expression profile and contain novel SAN enhancers, (2) Cis-regulation of Isl1 specifically in the SAN depends upon a conserved SAN enhancer that regulates PC development and SAN function, and (3) a corresponding human ISL1 enhancer may regulate human SAN function.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping