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Transcription factor ISL1 is essential for pacemaker development and function
Xingqun Liang, … , Yunfu Sun, Sylvia M. Evans
Xingqun Liang, … , Yunfu Sun, Sylvia M. Evans
Published July 20, 2015
Citation Information: J Clin Invest. 2015;125(8):3256-3268. https://doi.org/10.1172/JCI68257.
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Research Article Cardiology Development

Transcription factor ISL1 is essential for pacemaker development and function

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Abstract

The sinoatrial node (SAN) maintains a rhythmic heartbeat; therefore, a better understanding of factors that drive SAN development and function is crucial to generation of potential therapies, such as biological pacemakers, for sinus arrhythmias. Here, we determined that the LIM homeodomain transcription factor ISL1 plays a key role in survival, proliferation, and function of pacemaker cells throughout development. Analysis of several Isl1 mutant mouse lines, including animals harboring an SAN-specific Isl1 deletion, revealed that ISL1 within SAN is a requirement for early embryonic viability. RNA-sequencing (RNA-seq) analyses of FACS-purified cells from ISL1-deficient SANs revealed that a number of genes critical for SAN function, including those encoding transcription factors and ion channels, were downstream of ISL1. Chromatin immunoprecipitation assays performed with anti-ISL1 antibodies and chromatin extracts from FACS-purified SAN cells demonstrated that ISL1 directly binds genomic regions within several genes required for normal pacemaker function, including subunits of the L-type calcium channel, Ank2, and Tbx3. Other genes implicated in abnormal heart rhythm in humans were also direct ISL1 targets. Together, our results demonstrate that ISL1 regulates approximately one-third of SAN-specific genes, indicate that a combination of ISL1 and other SAN transcription factors could be utilized to generate pacemaker cells, and suggest ISL1 mutations may underlie sick sinus syndrome.

Authors

Xingqun Liang, Qingquan Zhang, Paola Cattaneo, Shaowei Zhuang, Xiaohui Gong, Nathanael J. Spann, Cizhong Jiang, Xinkai Cao, Xiaodong Zhao, Xiaoli Zhang, Lei Bu, Gang Wang, H.S. Vincent Chen, Tao Zhuang, Jie Yan, Peng Geng, Lina Luo, Indroneal Banerjee, Yihan Chen, Christopher K. Glass, Alexander C. Zambon, Ju Chen, Yunfu Sun, Sylvia M. Evans

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Figure 1

Expression of ISL1 in pacemaker cells of the SAN during development and after birth.

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Expression of ISL1 in pacemaker cells of the SAN during development and ...
ISL1 was coexpressed with HCN4 in myocardium of the SV at E9.5 (A), and in the majority of SAN cells from E10.5–P7 (B–G). ISL1 expression did not overlap with Cx40, which is expressed in atrial myocardium (E and G). The boxed area in H delineates regions depicted in F and G. The fraction of HCN4 cells that expressed Isl1 remained constant at early stages from E11.5–E14.5, but decreased at E18 (I). After birth, the fraction of HCN4 cells that expressed Isl1 decreased significantly (I). n = 4, P < 0.05, 2-tailed t test. svc, superior vena cava; ra, right atria; lv, left ventricle; rv, right ventricle. Scale bars as shown.

Copyright © 2022 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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