Ontology highlight
ABSTRACT:
PROVIDER: PRJNA531964 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR8879060_1.fastq.gz | Fastqsanger.gz | |||
| SRR8879060_2.fastq.gz | Fastqsanger.gz | |||
| SRR8879061_1.fastq.gz | Fastqsanger.gz | |||
| SRR8879061_2.fastq.gz | Fastqsanger.gz | |||
| SRR8879056_1.fastq.gz | Fastqsanger.gz |
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Project description:Oligogenic inheritance of congenital heart disease involving a NKX2-5 modifier
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Project description:Hypoplastic left heart syndrome (HLHS) is the most lethal congenital heart disease (CHD). The pathogenesis of HLHS is poorly understood and due to the likely oligogenic complexity of the disease, definitive HLHS-causing genes have not yet been identified. Postulating that impaired cardiomyocyte proliferation as a likely important contributing mechanism to HLHS pathogenesis, and we conducted a genome-wide siRNA screen to identify genes affecting proliferation of human iPSC-derived cardiomyocytes (hPSC-CMs). This yielded ribosomal protein (RP) genes as the most prominent class of effectors of CM proliferation. In parallel, whole genome sequencing and rare variant filtering of a cohort of 25 HLHS proband-parent trios with poor clinical outcome revealed enrichment of rare variants of RP genes. In addition, in another familial CHD case of HLHS proband we identified a rare, predicted-damaging promoter variant affecting RPS15A that was shared between the proband and a distant relative with CHD. Functional testing with an integrated multi-model system approach reinforced the idea that RP genes are major regulators of cardiac growth and proliferation, thus potentially contributing to hypoplastic phenotype observed in HLHS patients. Cardiac knockdown (KD) of RP genes with promoter or coding variants (RPS15A, RPS17, RPL26L1, RPL39, RPS15) reduced proliferation in generic hPSC-CMs and caused malformed hearts, heart-loss or even lethality in Drosophila. In zebrafish, diminished rps15a function caused reduced CM numbers, heart looping defects, or weakened contractility, while reduced rps17 or rpl39 function caused reduced ventricular size or systolic atrial dysfunction, respectively. Importantly, genetic interactions between RPS15A and core cardiac transcription factors TBX5 in CMs, Drosocross, pannier and tinman in flies, and tbx5 and nkx2-7 (nkx2-5 paralog) in fish, support a specific role for RP genes in heart development. Furthermore, RPS15A KD-induced heart/CM proliferation defects were significantly attenuated by p53 KD in both hPSC-CMs and zebrafish, and by Hippo activation (YAP/yorkie overexpression) in developing fly hearts. Based on these findings, we conclude that RP genes play critical roles in cardiogenesis and constitute an emerging novel class of gene candidates likely involved in HLHS and other CHDs.
2022-07-14 | GSE207658 | GEO
Project description:Environmentally induced epigenetic transgenerational inheritance of adult onset disease involves a variety of phenotypic changes suggesting a general alteration in genome activity. Investigation of eleven different tissue transcriptomes in male and female F3 generation vinclozolin versus control lineage rats demonstrated all tissues examined had unique transgenerational transcriptomes. Common cellular pathways and processes were identified among the tissues. A bionetwork analysis identified gene modules with coordinated gene expression and each had unique gene networks regulating tissue specific gene expression and function. A large number of statistically significant over-represented clusters of differentially expressed genes were identified and termed M-bM-^@M-^\Epigenetic Control RegionsM-bM-^@M-^]. Combined observations demonstrate that all tissues derived from the epigenetically altered germ line develop transgenerational transcriptomes unique to the tissue, but common epigenetic control regions in the genome appear to in part coordinately regulate these tissue specific transcriptomes. This systems biology approach provides insight into the molecular mechanisms involved in the epigenetic transgenerational inheritance of a variety of adult onset disease phenotypes. We used microarrays to determine genes expressed differentially in rats 11 male or female smatic tissues -male heart, kidney, liver, testis, prostate, seminal vesicles; female heart, kidney, liver, ovary, uterus - due to Vinclozolin treatments of their grand-grandmothers. For each of 11 male or female smatic tissues, RNA samples from 2 treatment groups - control (Con) and vinclozolin (Vin) - were compared to each other. Each treatment groups contained 3 biological replica. RNA for each replica was pooled from 2 individual animals.
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Project description:Environmentally induced epigenetic transgenerational inheritance of adult onset disease involves a variety of phenotypic changes suggesting a general alteration in genome activity. Investigation of eleven different tissue transcriptomes in male and female F3 generation vinclozolin versus control lineage rats demonstrated all tissues examined had unique transgenerational transcriptomes. Common cellular pathways and processes were identified among the tissues. A bionetwork analysis identified gene modules with coordinated gene expression and each had unique gene networks regulating tissue specific gene expression and function. A large number of statistically significant over-represented clusters of differentially expressed genes were identified and termed “Epigenetic Control Regions”. Combined observations demonstrate that all tissues derived from the epigenetically altered germ line develop transgenerational transcriptomes unique to the tissue, but common epigenetic control regions in the genome appear to in part coordinately regulate these tissue specific transcriptomes. This systems biology approach provides insight into the molecular mechanisms involved in the epigenetic transgenerational inheritance of a variety of adult onset disease phenotypes. We used microarrays to determine genes expressed differentially in rats 11 male or female smatic tissues -male heart, kidney, liver, testis, prostate, seminal vesicles; female heart, kidney, liver, ovary, uterus - due to Vinclozolin treatments of their grand-grandmothers.
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