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Loss of RNA expression and allele-specific expression associated with congenital heart disease.

ABSTRACT: Congenital heart disease (CHD), a prevalent birth defect occurring in 1% of newborns, likely results from aberrant expression of cardiac developmental genes. Mutations in a variety of cardiac transcription factors, developmental signalling molecules and molecules that modify chromatin cause at least 20% of disease, but most CHD remains unexplained. We employ RNAseq analyses to assess allele-specific expression (ASE) and biallelic loss-of-expression (LOE) in 172 tissue samples from 144 surgically repaired CHD subjects. Here we show that only 5% of known imprinted genes with paternal allele silencing are monoallelic versus 56% with paternal allele expression-this cardiac-specific phenomenon seems unrelated to CHD. Further, compared with control subjects, CHD subjects have a significant burden of both LOE genes and ASE events associated with altered gene expression. These studies identify FGFBP2, LBH, RBFOX2, SGSM1 and ZBTB16 as candidate CHD genes because of significantly altered transcriptional expression.

SUBMITTER: McKean DM

PROVIDER: S-EPMC5052634 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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Loss of RNA expression and allele-specific expression associated with congenital heart disease.

McKean David M DM Homsy Jason J Wakimoto Hiroko H Patel Neil N Gorham Joshua J DePalma Steven R SR Ware James S JS Zaidi Samir S Ma Wenji W Patel Nihir N Lifton Richard P RP Chung Wendy K WK Kim Richard R Shen Yufeng Y Brueckner Martina M Goldmuntz Elizabeth E Sharp Andrew J AJ Seidman Christine E CE Gelb Bruce D BD Seidman J G JG

Nature communications 20160927

Congenital heart disease (CHD), a prevalent birth defect occurring in 1% of newborns, likely results from aberrant expression of cardiac developmental genes. Mutations in a variety of cardiac transcription factors, developmental signalling molecules and molecules that modify chromatin cause at least 20% of disease, but most CHD remains unexplained. We employ RNAseq analyses to assess allele-specific expression (ASE) and biallelic loss-of-expression (LOE) in 172 tissue samples from 144 surgically ...[more]

PMID: 27670201

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Project description:Genome-wide association studies have identified a coronary artery disease (CAD) risk locus in a non-coding region at 9p21.3, the nearest genes being CDKN2A and CDKN2B. To understand the pathways by which this locus might influence CAD susceptibility, we investigated associations between the 9p21.3 risk genotype and global gene expression in heart tissue from donors with no diagnosed heart disease (n?=?108, predominant cause of death, cerebral vascular accident) and in carotid plaque (n?=?106), aorta (n?=?104) and mammary artery (n?=?88) tissues from heart valve and carotid endarterectomy patients. Genotyping was performed with Taqman assays and Illumina arrays, and gene expression profiles generated with Affymetrix microarrays. Associations were analyzed with an additive genetic model. In heart tissue, 46 genes were putatively altered in association with the 9p21.3 risk allele (70% down-regulated, fold-change >1.1 per allele, p<0.05 adjusted for age, gender, ethnicity, cause of death). These genes were enriched for biomarkers of myocardial infarction (p?=?1.53×10(-9)), response to wounding (p?=?2.65×10(-10)) and inflammatory processes (p<1.97×10(-7)). Among the top 10 most down-regulated genes, 7 genes shared a set of transcription factor binding sites within conserved promoter regions (p<1.14×10(-5)), suggesting they may be co-regulated. Canonical pathway modelling of the most differentially expressed transcripts across all tissues (154 genes, 60% down-regulated, fold-change >1.1 per allele, p<0.01) showed that 75% of the genes could be transcriptionally regulated through the cell cycle G1 phase progression pathway (p<1.08×10(-258)), in which CDKN2A and CDKN2B play a regulatory role. These data suggest that the cell cycle G1 phase progression pathway is activated in individuals with the 9p21.3 risk allele. This may contribute to a proliferative phenotype that promotes adverse cardiac hypertrophy and vascular remodeling, leading to an increased CAD risk.

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Loss of RNA expression and allele-specific expression associated with congenital heart disease.

Publications

Loss of RNA expression and allele-specific expression associated with congenital heart disease.

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