Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA284245 | ENA |
REPOSITORIES: ENA
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Project description: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. ISL1 ChIP-seq profiling was performed in Hcn4-H2BGFP SAN cells purified from neonatal hearts.
2015-07-23 | E-GEOD-68974 | biostudies-arrayexpress
Project description: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.
2015-07-23 | GSE68974 | GEO
Project description:Genome-wide chromatin-immunoprecipitation studies of sympathetic neurons reveals critical direct targets of ISL1 and suggests potential co-factor families for ISL1 action in sympathetic neurons
| PRJNA360584 | ENA
Project description: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. Analysis of several Isl1 mutant mouse lines, including one in which Isl1 was specifically ablated in SAN (Hcn4- CreERT2;Isl1) revealed an early requirement for Isl1 within SAN for embryonic viability. RNA-seq analyses on FACS purified SAN cells revealed dysregulation of a number of genes critical for SAN function to be downstream of ISL1 in Hcn4-CreERT2;Isl1 mutants, including transcription factors and ion channels. Our studies demonstrated that ISL1 regulated approximately one third of genes that were significantly expressed in SAN, 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. Results also suggest Isl1 as a candidate gene for sick sinus syndrome.
2015-07-24 | GSE69097 | GEO
Project description: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. Analysis of several Isl1 mutant mouse lines, including one in which Isl1 was specifically ablated in SAN (Hcn4- CreERT2;Isl1) revealed an early requirement for Isl1 within SAN for embryonic viability. RNA-seq analyses on FACS purified SAN cells revealed dysregulation of a number of genes critical for SAN function to be downstream of ISL1 in Hcn4-CreERT2;Isl1 mutants, including transcription factors and ion channels. Our studies demonstrated that ISL1 regulated approximately one third of genes that were significantly expressed in SAN, 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. Results also suggest Isl1 as a candidate gene for sick sinus syndrome. RNA-seq analyses were performed on samples from Hcn4-CreERT2;Isl1 mutant and control SANs
2015-07-24 | E-GEOD-69097 | biostudies-arrayexpress
Project description: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, 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. We used ATAC-Seq on sorted neonatal mouse SAN to define regions of open chromatin in PCs and neighboring right atrial cardiomyocytes. PC-specific ATAC-seq peaks were located near established SAN genes and were enriched for distinct sets of transcription factor binding sites. In-vivo testing of a novel ATAC-seq peak at the Isl1 locus defined a regulatory element that was active specifically in the cardiac inflow at E8.5 and throughout later SAN development and maturation. Deletion of the enhancer uncovered a role for this cis-regulatory element in SAN development and function. 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.
2020-10-12 | GSE148515 | GEO
Project description:RNA Sequencing of Mouse Sinoatrial Node Reveals an Upstream Regulatory Role for Islet-1 in Cardiac Pacemaker Cells Rationale: Treatment of sinus node disease with regenerative or cell-based therapies will require a detailed understanding of gene regulatory networks in cardiac pacemaker cells (PCs). Objective: To characterize the transcriptome of PCs using RNA sequencing, and to identify transcriptional networks responsible for PC gene expression. Methods and Results: We used laser capture micro-dissection (LCM) on a sinus node reporter mouse line to isolate RNA from PCs for RNA sequencing (RNA-Seq). Differential expression and network analysis identified novel SAN-enriched genes, and predicted that the transcription factor Islet-1 (Isl1) is active in developing pacemaker cells. RNA-Seq on SAN tissue lacking Isl1 established that Isl1 is an important transcriptional regulator within the developing SAN. Conclusions: (1) The PC transcriptome diverges sharply from other cardiomyocytes; (2) Isl1 is a positive transcriptional regulator of the PC gene expression program. There are 25 RNA-Sequencing Samples
2015-02-06 | E-GEOD-65658 | biostudies-arrayexpress
Project description:RNA Sequencing of Mouse Sinoatrial Node Reveals an Upstream Regulatory Role for Islet-1 in Cardiac Pacemaker Cells Rationale: Treatment of sinus node disease with regenerative or cell-based therapies will require a detailed understanding of gene regulatory networks in cardiac pacemaker cells (PCs). Objective: To characterize the transcriptome of PCs using RNA sequencing, and to identify transcriptional networks responsible for PC gene expression. Methods and Results: We used laser capture micro-dissection (LCM) on a sinus node reporter mouse line to isolate RNA from PCs for RNA sequencing (RNA-Seq). Differential expression and network analysis identified novel SAN-enriched genes, and predicted that the transcription factor Islet-1 (Isl1) is active in developing pacemaker cells. RNA-Seq on SAN tissue lacking Isl1 established that Isl1 is an important transcriptional regulator within the developing SAN. Conclusions: (1) The PC transcriptome diverges sharply from other cardiomyocytes; (2) Isl1 is a positive transcriptional regulator of the PC gene expression program.
2015-02-06 | GSE65658 | GEO
Project description:Glucose homeostasis is dependent on functional pancreatic α and ß cells. Mechanisms underlying generation and maturation of these endocrine cells remain unclear. Here, we unravel the molecular mode of action of ISL1 in controlling α cell fate and endocrine differentiation in the pancreas. By combining transgenic mouse models, transcriptomic and epigenomic profiling, we uncover that elimination of Isl1 results in a diabetic phenotype with a complete loss of α cells, disrupted pancreatic islet architecture, downregulation of maturation markers of ß cells, and an enrichment in an intermediate endocrine progenitor transcriptomic profile. Mechanistically, apart from the altered transcriptome of pancreatic endocrine cells, Isl1 elimination results in altered silencing H3K27me3 histone modifications in the promoter regions of the essential genes for endocrine cell differentiation. Our results thus show that ISL1 transcriptionally and epigenetically controls α cell fate competence, and ß cell maturation, suggesting that ISL1 is a critical component for generating functional α and ß cells.
2022-06-17 | GSE206093 | GEO
Project description:Glucose homeostasis is dependent on functional pancreatic α and ß cells. Mechanisms underlying generation and maturation of these endocrine cells remain unclear. Here, we unravel the molecular mode of action of ISL1 in controlling α cell fate and endocrine differentiation in the pancreas. By combining transgenic mouse models, transcriptomic and epigenomic profiling, we uncover that elimination of Isl1 results in a diabetic phenotype with a complete loss of α cells, disrupted pancreatic islet architecture, downregulation of maturation markers of ß cells, and an enrichment in an intermediate endocrine progenitor transcriptomic profile. Mechanistically, apart from the altered transcriptome of pancreatic endocrine cells, Isl1 elimination results in altered silencing H3K27me3 histone modifications in the promoter regions of the essential genes for endocrine cell differentiation. Our results thus show that ISL1 transcriptionally and epigenetically controls α cell fate competence, and ß cell maturation, suggesting that ISL1 is a critical component for generating functional α and ß cells.
2022-06-17 | GSE206092 | GEO