GSE68974
Genome-wide chromatin-immunoprecipitation studies of purified SAN cells reveals critical direct targets of ISL1 and suggests potential co-factor families for ISL1 action in SAN cells
Understanding factors that drive development and function of the sinoatrial node (SAN) is crucial to development of potential therapies for sinus arrhythmias, including potential generation of biological pacemakers. Here, we identify a key cell autonomous role for the LIM homeodomain transcription factor ISL1 for survival, proliferation and function of pacemaker cells throughout development. Chromatin immunoprecipitation assays performed utilizing antibody to ISL1 in chromatin extracts from FACS purified SAN cells demonstrated that ISL1 directly binds genomic regions within several genes critical 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 downstream targets of ISL1 in SAN cells. Our studies represent the first in vivo ChIP-seq studies for SAN cells which provide a basis for further exploration of factors critical to SAN formation and function and highlight the potential for utilization of ISL1 in combination with other SAN transcription factors for generating pacemaker cells for therapy or drug screening purposes. Overall design: ISL1 ChIP-seq profiling was performed in Hcn4-H2BGFP SAN cells purified from neonatal hearts.