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Genome-wide mRNA expression analyses revealed dysregulation of genes important for SAN function in Hcn4-CreERT2;Isl1 mutants.

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE69097 | GEO | 2015/07/24

SECONDARY ACCESSION(S): PRJNA284529

REPOSITORIES: GEO

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Genome-wide mRNA expression analyses revealed dysregulation of genes important for SAN function in Hcn4-CreERT2;Isl1 mutants.

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

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

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

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

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

Mouse sinoatrial node transcriptome

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

Mouse sinoatrial node transcriptome

2015-02-06 | GSE65658 | GEO

Odz4 upregulates SAN-specific genes to promote differentiation into cardiac pacemaker-like cells

Project description:Cardiac arrhythmias stemming from abnormal sinoatrial node (SAN) function can lead to sudden death. Developing a biological pacemaker device for treating sick sinus syndrome (SSS) could offer a potential cure. Understanding SAN differentiation is crucial, yet its regulatory mechanism remains unclear. We reanalyzed published RNA-seq data and identified Odz4 as a SAN-specific candidate. In situ hybridization revealed Odz4 expression in the cardiac crescent and throughout the cardiac conduction system (CCS). To assess role of Odz4 in CCS differentiation, we utilized a Tet-Off inducible system for its intracellular domain (ICD). Odz4-ICD exogenously expressing embryonic bodies (EBs) exhibited an increased propensity to develop into pacemaker-like cells with enhanced automaticity and upregulated expression of SAN-specific genes. CellChat and GO analyses unveiled SAN-specific enrichment of ligand-receptor sets, especially Ptn-Ncl, and extracellular matrix components in the Odz4-ICD exogenously expressing group. Our findings underscore the significance of Odz4 in SAN development and offer fresh insights into biological pacemaker establishment

2024-07-07 | GSE271665 | GEO

Transcriptome profile of the zebrafish sinoatrial ring

Project description:Sino Atrial Node (SAN) is part of the cardiac conduction system, which controls the rhythmic contraction of the vertebrate heart. SAN consists of a specialized pacemaker cell population that has the potential to generate electrical impulses. Although SAN pacemakers have been extensively studied in mammalian and teleost models, including the zebrafish, their molecular nature remains inadequately comprehended. Here, we utilized the zebrafish transgenic line sqet33mi59BEt to isolate cells of the sino-atrial ring (SAR) of developing zebrafish embryos and profiled their transcriptome. Our analyses identified novel candidate genes and well-known conserved signaling pathways (Wnt, BMP) involved in pacemaker development. We show that the zebrafish SAR expresses several mammalian SAN pacemaker signature genes, which include hcn4 and calcium and potassium gated channels. Moreover, genes encoding components of the BMP and Wnt signaling pathways, as well as members of the Tbx family, which have previously been implicated in pacemaker development, were also overexpressed in the SAR. Among SAR-overexpressed genes, 24 had human homologues implicated in 104 different ClinVar phenotype entries related to various forms of congenital heart diseases. Moreover, we show that loss-of-function of three SAR-overexpressed genes, pard6a, prom2, and atp1a1a.2, resulted in abnormal heart morphology and physiology. Our results suggest the relevance of our transcriptomics resource to studying human heart conditions.

2021-09-10 | GSE160398 | GEO

Expression data from SAN tissue of WT and HCN4FEA mice

Project description:HCN4 channels are the major HCN channel isoform expressed in the sinoatrial node (SAN) and play a key role in cardiac pacemaking. We have characterized the gene expression profile in the SAN of adult mice expressing cAMP-insensitive HCN4 channels (HCN4FEA mice) in comparison to WT mice. In this dataset, we include the expression data obtained from dissected mouse SAN tissue of WT and HCN4FEA mice. These data are used to show that there are no relevant compensatory up- oder down-regulated genes in the SAN of HCN4FEA mice.

2020-09-11 | GSE138086 | GEO

Proteomics Couples Electrical Remodeling to Inflammation in a Murine Model of Heart Failure with Sinus Node Dysfunction

Project description:In patients with heart failure, concomitant sinus node dysfunction (SND) is an important predictor of mortality, yet its molecular underpinnings are poorly understood. Here, we acquired deep sinus node proteomes and phosphoproteomes in mice with heart failure and SND and report extensive remodelling. Intersecting the measured (phospho)proteome changes with human genomics and pharmacovigilance data highlighted downregulated proteins involved in electrical activity such as the pacemaker ion channel, Hcn4. We confirmed the importance of ion channel downregulation for sinus node physiology using computer modelling. Guided by the proteomics data, we hypothesized that an inflammatory response may drive the electrophysiological remodeling underlying SND in heart failure. In support of this, experimentally induced inflammation downregulated Hcn4 and slowed pacemaking in the isolated sinus node. From the proteomics data we identified proinflammatory cytokine-like protein galectin-3 as a potential target to mitigate the effect. Indeed, in-vivo suppression of galectin-3 in the animal model of heart failure prevented SND. Collectively, we outline the protein and phosphorylation remodeling of SND in heart failure, we highlight a role for inflammation in electrophysiological remodelling of the sinus node, and we present galectin-3 signalling as a target to ameliorate SND in heart failure.

2024-04-25 | PXD031084 | Pride

Baf250a orchestrates an epigenetic pathway to repress the Nkx2.5-directed contractile cardiomyocyte program in the sinoatrial node

Project description:We specifically deleted Baf250a in the SAN by using Hcn4-CreERT2 mice. We performed mRNA-seq to identify dysregulated genes in the SAN after deletion of Baf250a. To identify direct targets of Baf250a and sequential transcriptional events after deletion of Baf250a in the SAN, we performed mRNA-seq at 6 time points. i.e. 0 hr (tamoxifen treatment), 16 hr after tamoxifen treatment, 20 hr, 24 hr, 48 hr, and 6 days after tamoxifen treatment.

2016-03-22 | GSE55682 | GEO

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