Odz4 upregulates SAN-specific genes to promote differentiation into cardiac pacemaker-like cells
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1132731 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR29729105_1.fastq.gz | Fastqsanger.gz | |||
| SRR29729105_2.fastq.gz | Fastqsanger.gz | |||
| SRR29729106_1.fastq.gz | Fastqsanger.gz | |||
| SRR29729106_2.fastq.gz | Fastqsanger.gz |
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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
Project description:We established an efficient strategy to derive functional human SAN like pacemaker cells for disease modeling and drug screening. And we found SARS-CoV-2 infection causes dysfunction of human SAN like pacemaker cells and induces ferroptosis. And we also found that Deferoxamine and imatinib can block SARS-CoV-2 infection and infection-associated ferroptosis. Our study using functional human SAN like pacemaker cells demonstrates a potential mechanism for some COVID-19 cardiac abnormalities and identifies candidate drugs to protect the SAN like pacemaker from SARS-CoV-2 infection.
2022-01-26 | GSE193722 | GEO
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 the role of Odz4 in CCS differentiation, we utilized a Tet-Off inducible system for its intracellular domain (ICD). Embryonic bodies (EBs) exogenously expressing Odz4-ICD 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 group exogenously expressing Odz4-ICD. Our findings underscore the significance of Odz4 in SAN development and offer fresh insights into biological pacemaker establishment.
| S-EPMC11808419 | biostudies-literature
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.
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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.
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Project description:Gata4, Mef2c, Hand2, and Tbx5 (GHMT) can reprogram transduced fibroblasts into induced pacemaker-like myocytes (iPMs), but the underlying mechanisms remain obscure. Here we explored the role of Hand2 in iPM formation by using a combination of transcriptome, genome, and biochemical assays. We found many shared transcriptional signatures between iPMs and endogenous sinoatrial node (SAN), yet key regulatory networks remain missing. We demonstrate that Hand2 augments chromatin accessibility at loci involved in sarcomere organization, electrical coupling, and membrane depolarization. Focusing on an established cardiac Hand2 cistrome, we observe selective reorganization of chromatin accessibility to promote pacemaker-specific gene expression. Moreover, we identify a novel Hand2 cardiac subtype diversity (CSD) domain through biochemical analysis of the N-terminus. By integrating our RNA-seq and ATAC-seq datasets, we highlight desmosome organization as a hallmark feature of iPM formation. Collectively, our results illuminate Hand2-dependent mechanisms that may guide future efforts to rationally improve iPM formation.
2019-07-30 | GSE124337 | GEO
Project description:Gata4, Mef2c, Hand2, and Tbx5 (GHMT) can reprogram transduced fibroblasts into induced pacemaker-like myocytes (iPMs), but the underlying mechanisms remain obscure. Here we explored the role of Hand2 in iPM formation by using a combination of transcriptome, genome, and biochemical assays. We found many shared transcriptional signatures between iPMs and endogenous sinoatrial node (SAN), yet key regulatory networks remain missing. We demonstrate that Hand2 augments chromatin accessibility at loci involved in sarcomere organization, electrical coupling, and membrane depolarization. Focusing on an established cardiac Hand2 cistrome, we observe selective reorganization of chromatin accessibility to promote pacemaker-specific gene expression. Moreover, we identify a novel Hand2 cardiac subtype diversity (CSD) domain through biochemical analysis of the N-terminus. By integrating our RNA-seq and ATAC-seq datasets, we highlight desmosome organization as a hallmark feature of iPM formation. Collectively, our results illuminate Hand2-dependent mechanisms that may guide future efforts to rationally improve iPM formation.
2019-07-30 | GSE124336 | GEO
Project description:Each heartbeat is triggered by the sinoatrial node (SAN), the primary pacemaker of the heart. Studies in animal models have revealed that pacemaker cells share a common progenitor with the (pro)epicardium, and that the pacemaker cardiomyocytes further diversify into “transitional”, “tail” and “head” subtypes. However, the underlying molecular mechanisms, especially of human pacemaker cell development are poorly understood. Here, we performed single cell RNA sequencing (scRNA-seq) and trajectory inference on human induced pluripotent stem cells (hiPSCs) differentiating to SAN-like cardiomyocytes (SANCM) to construct a roadmap of transcriptional changes and lineage decisions. In differentiated SANCM, we identified distinct clusters that closely resemble different subpopulations of the in vivo SAN. Moreover, the presence of a side population of proepicardial cells suggested their shared ontogeny with SANCM, as also reported in vivo. Our results demonstrate that the divergence of SANCM and proepicardial lineages is determined by WNT signaling. Furthermore, we uncovered roles for TGFβ and WNT signaling in the branching of transitional and head SANCM subtypes, respectively. These findings provide new insights into the molecular processes involved in human pacemaker cell differentiation, opening new avenues for complex disease modeling in vitro and inform approaches for cell-therapy based regeneration of the SAN.
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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.
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Project description:The sinoatrial node regulates the heart rate throughout life. Failure of this primary pacemaker results in life-threatening, slow heart rhythm. Despite its important function, the cellular and molecular composition of the human sinoatrial node is not resolved. Particularly, no cell surface marker to identify and isolate sinoatrial node pacemaker cells has been reported. Here we use single-nuclei/cell RNA sequencing of fetal and human pluripotent stem cell-derived sinoatrial node cells and show that they consist of three subtypes of pacemaker cells, including Core Pacemaker, Sinus Venosus, and Transitional Cells. Our study identifies a host of sinoatrial node pacemaker markers including MYH11, BMP4, and the cell surface antigen CD34. We demonstrate that sorting for CD34+ cells from stem cell differentiation cultures enriches for sinoatrial node cells with a functional pacemaker phenotype. This sinoatrial node pacemaker cell surface marker is highly valuable for stem cell-based disease modelling, drug discovery, cell replacement therapies, as well as the delivery of therapeutics to sinoatrial node cells in vivo using antibody-drug conjugates.
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