Biology subjects

Yaacov, O.

Publications and source records attributed to Yaacov, O..

3 recordsLinked to original sources

bioRxiv2025

Massively parallel reporter assays identify functional enhancer variants at QT interval GWAS loci

Genome-wide association studies (GWAS) have identified >30 loci with multiple common noncoding variants explaining interindividual electrocardiographic QT interval (QTi) variation. Of the many types of noncoding functional elements, here we sought to identify transcriptional enhancers with sequence variation and their cognate transcription factors (TFs) that alter the expression of proximal cardiac genes to affect QTi variation. We used massively parallel reporter assays (MPRA) in mouse cardiomyocyte HL-1 cells to screen for functional enhancer variants among 1,018 QTi-associated GWAS variants that overlap candidate cardiac enhancers across 31 loci. We identified 445 GWAS variant-containing enhancers of which 79 showed significant allelic difference in enhancer activity across 21 GWAS loci, with multiple enhancer variants per locus. Of these, we predicted differential binding by cardiac TFs, including AP-1, ATF-1, GATA2, MEF2, NKX2.5, SRF and TBX5 which are known to play key roles in development and homeostasis, at 49 enhancer variants. Finally, we used expression quantitative trait locus mapping and predicted promoter-enhancer contacts to identify 14 candidate target genes through analyses of 36 enhancer variants at 16 loci. This study provides strong evidence for 14 cardiac genes, 10 of them novel, impacting on QTi variation, beyond explaining observed genetic associations.

genetics↗

bioRxiv2022

RET enhancer haplotype-dependent remodeling of the human fetal gut development program

Hirschsprung disease (HSCR) is associated with deficiency of the receptor tyrosine kinase RET, resulting in loss of cells of the enteric nervous system (ENS) during fetal gut development. The major contribution to HSCR risk is from common sequence variants in RET enhancers with additional risk from rare coding variants in many genes. Here, we demonstrate that these RET enhancer variants specifically alter the human fetal gut development program through significant decreases in gene expression of RET, members of the RET-EDNRB gene regulatory network (GRN), other HSCR genes, and an altered transcriptome with 2,382 differentially expressed genes with diverse neuronal and mesenchymal functions. A parsimonious hypothesis for these results is that beyond RETs direct effect on its GRN, it also has a major role in enteric neural crest derived cell (ENCDC) precursor proliferation, its deficiency reducing ENCDCs with relative expansion of non-ENCDC cells. Thus, genes reducing RET proliferative activity can potentially cause HSCR. One such class is the 23 RET-dependent transcription factors enriched in early gut development. We show that their knockdown in human neuroblastoma SK-N-SH cells reduces RET and/or EDNRB gene expression, expanding the RET-EDNRB GRN. The human embryos we studied had major remodeling of the gut transcriptional but were unlikely to have had HSCR: thus, genetic changes in addition to those in RET are required for a significant enough reduction in ENCDCs to cause aganglionosis.

genetics↗

bioRxiv2022

Tissue-specific and tissue-agnostic effects of genome sequence variation modulating blood pressure

Genome-wide association studies (GWAS) have mapped thousands of variants for numerous polygenic traits and diseases. However, with some exceptions, mechanistic understanding of which precise variants affect which genes in which tissues to modulate trait variation is still lacking. To this end, we introduce a novel class of genomic analyses applicable to any complex trait using GWAS together with gene expression and chromatin accessibility data from multiple tissues. Here we identify the transcription factors (TFs) and regulatory variants within active enhancers regulating specific genes in individual tissues to explain trait heritability of blood pressure (BP), a classical polygenic trait. We show that kidney-, adrenal-, heart-, and arterial-specific regulatory variants contribute to 2.5%, 5.3%, 7.7%, and 11.8% of variant heritability, respectively. Collectively, [~]500,000 predicted regulatory variants across these four tissues explain 33.4% of variant heritability. We demonstrate that these variants are enriched in enhancers binding specific TFs in each tissue. Our findings suggest that gene regulatory networks perturbed by common regulatory variants in a tissue relevant to a phenotype are the primary source of interindividual variation of BP. These studies provide an approach to scan each human tissue for its physiological contribution to a trait.

genetics↗