Dataset Information

Pathogenic variants damage cell composition and single cell transcription in cardiomyopathies.

ABSTRACT: Pathogenic variants in genes that cause dilated cardiomyopathy (DCM) and arrhythmogenic cardiomyopathy (ACM) convey high risks for the development of heart failure through unknown mechanisms. Using single-nucleus RNA sequencing, we characterized the transcriptome of 880,000 nuclei from 18 control and 61 failing, nonischemic human hearts with pathogenic variants in DCM and ACM genes or idiopathic disease. We performed genotype-stratified analyses of the ventricular cell lineages and transcriptional states. The resultant DCM and ACM ventricular cell atlas demonstrated distinct right and left ventricular responses, highlighting genotype-associated pathways, intercellular interactions, and differential gene expression at single-cell resolution. Together, these data illuminate both shared and distinct cellular and molecular architectures of human heart failure and suggest candidate therapeutic targets.

SUBMITTER: Reichart D

PROVIDER: S-EPMC9528698 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature

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Pathogenic variants damage cell composition and single cell transcription in cardiomyopathies.

Reichart Daniel D Lindberg Eric L EL Maatz Henrike H Miranda Antonio M A AMA Viveiros Anissa A Shvetsov Nikolay N Gärtner Anna A Nadelmann Emily R ER Lee Michael M Kanemaru Kazumasa K Ruiz-Orera Jorge J Strohmenger Viktoria V DeLaughter Daniel M DM Patone Giannino G Zhang Hao H Woehler Andrew A Lippert Christoph C Kim Yuri Y Adami Eleonora E Gorham Joshua M JM Barnett Sam N SN Brown Kemar K Buchan Rachel J RJ Chowdhury Rasheda A RA Constantinou Chrystalla C Cranley James J Felkin Leanne E LE Fox Henrik H Ghauri Ahla A Gummert Jan J Kanda Masatoshi M Li Ruoyan R Mach Lukas L McDonough Barbara B Samari Sara S Shahriaran Farnoush F Yapp Clarence C Stanasiuk Caroline C Theotokis Pantazis I PI Theis Fabian J FJ van den Bogaerdt Antoon A Wakimoto Hiroko H Ware James S JS Worth Catherine L CL Barton Paul J R PJR Lee Young-Ae YA Teichmann Sarah A SA Milting Hendrik H Noseda Michela M Oudit Gavin Y GY Heinig Matthias M Seidman Jonathan G JG Hubner Norbert N Seidman Christine E CE

Science (New York, N.Y.) 20220805 6606

Pathogenic variants in genes that cause dilated cardiomyopathy (DCM) and arrhythmogenic cardiomyopathy (ACM) convey high risks for the development of heart failure through unknown mechanisms. Using single-nucleus RNA sequencing, we characterized the transcriptome of 880,000 nuclei from 18 control and 61 failing, nonischemic human hearts with pathogenic variants in DCM and ACM genes or idiopathic disease. We performed genotype-stratified analyses of the ventricular cell lineages and transcription ...[more]

PMID: 35926050

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Project description:BackgroundDeficiency in DNA-damage repair (DDR) genes, often due to disruptive coding variants, is linked to higher cancer risk. Our previous study has revealed the association between rare loss-of-function variants in DDR genes and the risk of lung cancer. However, it is still challenging to study the predisposing role of rare regulatory variants of these genes.MethodsBased on whole-genome sequencing data from 2984 patients with non-small cell lung cancer (NSCLC) and 3020 controls, we performed massively parallel reporter assays on 1818 rare variants located in the promoters of DDR genes. Pathway- or gene-level burden analyses were performed using Firth's logistic regression or generalized linear model.FindingsWe identified 750 rare functional regulatory variants (frVars) that showed allelic differences in transcriptional activity within the promoter regions of DDR genes. Interestingly, the burden of frVars was significantly elevated in cases (odds ratio [OR] = 1.17, p = 0.026), whereas the burden of variants prioritized solely based on bioinformatics annotation was comparable between cases and controls (OR = 1.04, p = 0.549). Among the frVars, 297 were down-regulated transcriptional activity (dr-frVars) and 453 were up-regulated transcriptional activity (ur-frVars); especially, dr-frVars (OR = 1.30, p = 0.008) rather than ur-frVars (OR = 1.06, p = 0.495) were significantly associated with risk of NSCLC. Individuals with NSCLC carried more dr-frVars from Fanconi anemia, homologous recombination, and nucleotide excision repair pathways. In addition, we identified seven genes (i.e., BRCA2, GTF2H1, DDB2, BLM, ALKBH2, APEX1, and RAD51B) with promoter dr-frVars that were associated with lung cancer susceptibility.InterpretationOur findings indicate that functional promoter variants in DDR genes, in addition to protein-truncating variants, can be pathogenic and contribute to lung cancer susceptibility.FundingNational Natural Science Foundation of China, Youth Foundation of Jiangsu Province, Research Unit of Prospective Cohort of Cardiovascular Diseases and Cancer of Chinese Academy of Medical Sciences, and Natural Science Foundation of Jiangsu Province.

Project description:BackgroundGenome stability is maintained by the DNA damage repair (DDR) system composed of multiple DNA repair pathways of hundreds of genes. Germline pathogenic variation (PV) in DDR genes damages function of the affected DDR genes, leading to genome instability and high risk of diseases, in particular, cancer. Knowing evolutionary origin of the PVs in human DDR genes is essential to understand the etiology of human diseases. However, answer to the issue remains largely elusive. In this study, we analyzed evolutionary origin for the PVs in human DDR genes.MethodsWe identified 169 DDR genes by referring to various databases and identified PVs in the DDR genes of modern humans from ClinVar database. We performed a phylogenetic analysis to analyze the conservation of human DDR PVs in 100 vertebrates through cross-species genomic data comparison using the phyloFit program of the PHAST package and visualized the results using the GraphPad Prism software and the ggplot module. We identified DDR PVs from over 5000 ancient humans developed a database to host the DDR PVs ( https://genemutation.fhs.um.edu.mo/dbDDR-AncientHumans ). Using the PV data, we performed a molecular archeological analysis to compare the DDR PVs between modern humans and ancient humans. We analyzed evolution selection of DDR genes across 20 vertebrates using the CodeML in PAML for phylogenetic analysis.ResultsOur phylogenic analysis ruled out cross-species conservation as the origin of human DDR PVs. Our archeological approach identified rich DDR PVs shared between modern and ancient humans, which were mostly dated within the last 5000 years. We also observed similar pattern of quantitative PV distribution between modern and ancient humans. We further detected a set of ATM, BRCA2 and CHEK2 PVs shared between human and Neanderthals.ConclusionsOur study reveals that human DDR PVs mostly arose in recent human history. We propose that human high cancer risk caused by DDR PVs can be a by-product of human evolution.

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Pathogenic variants damage cell composition and single cell transcription in cardiomyopathies.

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Pathogenic variants damage cell composition and single cell transcription in cardiomyopathies.

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