Single cell RNA-sequencing (scRNA-seq) of ISL1 knockout (KO) or knockdown and NKX2.5 KO compared to WT in cardiac progenitors (CPs); scRNA-seq of ISL1 KO compared to WT in motor neuron progenitors (MNPs)
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE223339 | GEO | 2023/10/17
REPOSITORIES: GEO
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Project description:The LIM-homeodomain transcription factor ISL1 marks multipotent cardiac progenitors that give rise to cardiac muscle, endothelium, and smooth muscle cells. ISL1+ progenitors can be derived from human pluripotent stem cells, but the inability to efficiently isolate pure populations has limited their characterization. Using a genetic selection strategy, we were able to highly enrich ISL1+ cells derived from human embryonic stem cells. Comparative quantitative proteomic analysis of enriched ISL1+ cells identified ALCAM (CD166) as a surface marker that enabled the isolation of ISL1+ progenitor cells. ALCAM+/ISL1+ progenitors are multipotent and differentiate into cardiomyocytes, endothelial cells, and smooth muscle cells. Transplantation of ALCAM+ progenitors enhances tissue recovery, restores cardiac function and improves angiogenesis through activation of AKT-MAPK signaling in a rat model of myocardial infarction, based on cardiac MRI and histology. Our study establishes a new efficient method for scalable purification of human ISL1+ cardiac precursor cells for therapeutic applications.
2018-01-19 | GSE109339 | GEO
Project description:The transcription factor ISL1 is expressed in pituitary gland stem cells and the thyrotrope and gonadotrope lineages. Pituitary-specific Isl1 deletion causes hypopituitarism with increased stem cell apoptosis, reduced differentiation of thyrotropes and gonadotropes, and reduced body size. Conditional Isl1 deletion causes development of multiple Rathke’s cleft-like cysts, with 100% penetrance. Foxa1 and Foxj1 are abnormally expressed in the pituitary gland and associated with a ciliogenic gene expression program in the cysts. We confirmed expression of FOXA1, FOXJ1 and stem cell markers in human Rathke's cleft cyst tissue, but not craniopharyngiomas, which suggests these transcription factors are useful, pathological markers for diagnosis of Rathke's cleft cysts. These studies support a model whereby expression of ISL1 in pituitary progenitors drives differentiation into thyrotropes and gonadotropes, and without it, activation of FOXA1 and FOXJ1 permits development of an oral epithelial cell fate with mucinous cysts. This pituitary-specific Isl1 mouse knockout sheds light on the etiology of Rathke's cleft cysts and the role of ISL1 in normal pituitary development.
2020-04-22 | GSE149019 | GEO
Project description:ChIP-sequencing demonstrated that ISL1 binds cardiac DNA in a cell-type-specific manner, and that NKX2.5 is both necessary and sufficient for this localization.
2023-10-17 | GSE195474 | GEO
Project description:Congenital heart disease (CHD) is a leading cause of infant mortality in the US and is commonly thought to arise from perturbations of transcription factors (TFs) during cardiac development. ISLET1 (ISL1) is one such TF, although it also directs differentiation of other cell types, including motor neuron progenitors (MNPs) and pancreatic islet cells. Although cellular specificity of ISL1 function is likely achieved through combinatorial interactions, its essential cardiac interacting partners are unknown. By assaying ISL1 genomic occupancy in human iPSC-derived cardiac progenitors (CPs) or MNPs and leveraging the deep learning approach BPNet, we identified cell-type-specific motifs of other TFs that predicted ISL1 occupancy in each lineage, with the NKX2.5 motif being most closely associated to ISL1 in CPs. We demonstrated ISL1 forms a protein complex with NKX2.5 in CPs, and the two regulated similar gene networks. NKX2.5 co-occupied more than half of ISL1-bound loci, and ISL1 was dependent on NKX2.5 for CP-specific localization. Furthermore, overexpression of NKX2.5 in MNPs led to ISL1 redistribution to CP-specific loci. These results reveal how ISL1 can guide differential lineage choices through a combinatorial code that dictates genomic occupancy and transcription.
2023-10-17 | PXD031059 | panorama
Project description:Rathke’s Cleft-Like Cysts Arise From Isl1 Deletion in Murine Pituitary Progenitors
| PRJNA627154 | ENA
Project description:Human pluripotent stem cells (hPSCs) offer a unique cellular model to study lineage specifications of the primary germ layers during human development. We profiled single-cell RNA-seq (scRNA-seq) on four lineage-specific progenitor cells derived from hESCs. Our scRNA-seq analyses revealed each type of progenitors display various extend of heterogeneity. Specifically, definitive endoderm cells (DECs) not only show a greater degree of heterogeneity, but are also enriched in metabolic signatures. Followed by detailed temporal scRNA-seq profiling along DEC differentiation, we reconstructed a differentiation trajectory using a novel statistical pipeline named Wave-Crest. Wave-Crest further identifies candidate regulators during the transitioning phase from Brachyury (T)+ mesendoderm towards CXCR4+ DEC state. To functionally test identified novel regulators; we generated a live cell monitoring system, a T-2A-EGFP knock-in reporter cell line via CRISPR/CAS9. We demonstrated that, among the top candidate genes, KLF8 plays a pivotal role modulating mesendoderm to DEC differentiation. In this submission, 1810 raw fastq files are provided; 212 are re-analysis from GSE64016. Four expected count matrices are provided - 1) 1018 single cells from snapshot progenitors; 2) 758 single cells from time couse profiling; 3) 19 bulk RNA-seq sample from snapshot progenitors; 4) 15 bulk RNA-seq sample from time course profiling. Total 1018 single cells from snapshot progenitors and 758 single cells from time couse profiling. Matchd population bulk RNA-seq samples for both the progenitors snapshot (19 samples) and time course profiling (15 samples) also included in this submission. These data set are used to detect the transitioning phase from mesendoderm to definitive endoderm.
2016-07-21 | E-GEOD-75748 | biostudies-arrayexpress
Project description:Visceral fat (VF) and subcutaneous fat (SF) are developmentally different tissues with different gene expression. Islet-1 (ISL1), a LIM-homeobox transcription factor with important developmental and regulatory function in islet, neural, and cardiac tissue, is virtually absent in SF but substantially expressed in the stromovascular [preadipocyte containing] fraction of VF; expression correlates negatively with adiposity in rodents and man. ISL1 expression is transiently increased in 3T3-L1 preadipocytes during early differentiation, suggesting a functional role. To examine the role of ISL1 in adipogenesis, we tested whether retroviral overexpression of ISL1 in 3T3-L1 preadipocytes affected their ability to differentiate into mature adipocytes. Terminal differentiation was assessed by Oil Red O [lipid droplet] staining and by immunoblot detection of adipocyte marker proteins, including aP2 and GLUT4. ISL1 significantly inhibited lipid droplet formation, reduced lipid accumulation (about 80% inhibition, p<0.05), and substantially inhibited aP2 and GLUT4 expression. ISL1 did not inhibit expression of C/EBPb and C/EBPd after induction of differentiation, but reduced PPARg and C/EBPa by >50% at both mRNA and protein level. In addition, the PPARg agonist, rosiglitazone, substantially rescued ISL1 inhibited adipogenesis in the absence of exogenous PPARg, and fully rescued in the presence of exogenous PPARg. In summary, ISL1 overexpression inhibited fat droplet formation, lipid accumulation, and adipocyte-specific gene expression; there was accompanying inhibition of C/EBPa, PPARg and downstream gene expression. We conclude that ISL1 overexpression inhibited adipocyte differentiation by inhibition of PPARg regulated gene expression. As abdominal obesity strongly correlates with insulin resistance, and cardiovascular risk, ISL1 up-regulation may impact abdominal obesity and its concomitant metabolic derangements. Total cellular RNA was isolated from 3T3-L1 cells expressing Flag-ISL1 or not at 48 h following treatment with differentiation cocktail. Individual RNA from biological triplicates was used for microarray analysis.
2012-09-05 | E-GEOD-40565 | 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. ISL1 ChIP-seq profiling was performed in Hcn4-H2BGFP SAN cells purified from neonatal hearts.
2015-07-23 | E-GEOD-68974 | biostudies-arrayexpress