title: Transcription factor ISL1 is essential for pacemaker development and function.
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.forename: Xingqun
authors.initials: X
authors.lastname: Liang
authors.forename: Qingquan
authors.initials: Q
authors.lastname: Zhang
authors.forename: Paola
authors.initials: P
authors.lastname: Cattaneo
authors.forename: Shaowei
authors.initials: S
authors.lastname: Zhuang
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Gong
authors.forename: Nathanael J
authors.initials: NJ
authors.lastname: Spann
authors.forename: Cizhong
authors.initials: C
authors.lastname: Jiang
authors.forename: Xinkai
authors.initials: X
authors.lastname: Cao
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Zhao
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Zhang
authors.forename: Lei
authors.initials: L
authors.lastname: Bu
authors.forename: Gang
authors.initials: G
authors.lastname: Wang
authors.forename: H S Vincent
authors.initials: HS
authors.lastname: Chen
authors.forename: Tao
authors.initials: T
authors.lastname: Zhuang
authors.forename: Jie
authors.initials: J
authors.lastname: Yan
authors.forename: Peng
authors.initials: P
authors.lastname: Geng
authors.forename: Lina
authors.initials: L
authors.lastname: Luo
authors.forename: Indroneal
authors.initials: I
authors.lastname: Banerjee
authors.forename: Yihan
authors.initials: Y
authors.lastname: Chen
authors.forename: Christopher K
authors.initials: CK
authors.lastname: Glass
authors.forename: Alexander C
authors.initials: AC
authors.lastname: Zambon
authors.forename: Ju
authors.initials: J
authors.lastname: Chen
authors.forename: Yunfu
authors.initials: Y
authors.lastname: Sun
authors.forename: Sylvia M
authors.initials: SM
authors.lastname: Evans
mesh_terms: D000818:Animals; D017487:Ankyrins / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation / Q000502:physiology*; D002470:Cell Survival; D002843:Chromatin / Q000235:genetics / Q000378:metabolism; D017353:Gene Deletion; D018507:Gene Expression Regulation, Developmental / Q000502:physiology*; D060850:LIM-Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009200:Myocardial Contraction / Q000502:physiology*; D011485:Protein Binding; D012804:Sick Sinus Syndrome / Q000196:embryology / Q000235:genetics / Q000473:pathology; D012849:Sinoatrial Node / Q000166:cytology / Q000196:embryology*; D020825:T-Box Domain Proteins / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: C498995:Ank2 protein, mouse; D017487:Ankyrins; D002843:Chromatin; D060850:LIM-Homeodomain Proteins; D020825:T-Box Domain Proteins; C491460:Tbx3 protein, mouse; D014157:Transcription Factors; C063843:insulin gene enhancer binding protein Isl-1