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Identification of the Molecular Components of Enhancer-Mediated Gene Expression Variation in Multiple Tissues Regulating Blood Pressure

Yaacov, Or; Mathiyalagan, Prabhu; Berk-Rauch, Hanna E; Ganesh, Santhi K; Zhu, Luke; Hoffmann, Thomas J; Iribarren, Carlos; Risch, Neil; Lee, Dongwon; Chakravarti, Aravinda
BACKGROUND/UNASSIGNED:Inter-individual variation in blood pressure (BP) arises in part from sequence variants within enhancers modulating the expression of causal genes. We propose that these genes, active in tissues relevant to BP physiology, can be identified from tissue-level epigenomic data and genotypes of BP-phenotyped individuals. METHODS/UNASSIGNED:We used chromatin accessibility data from the heart, adrenal, kidney, and artery to identify cis-regulatory elements (CREs) in these tissues and estimate the impact of common human single-nucleotide variants within these CREs on gene expression, using machine learning methods. To identify causal genes, we performed a gene-wise association test. We conducted analyses in 2 separate large-scale cohorts: 77 822 individuals from the Genetic Epidemiology Research on Adult Health and Aging and 315 270 individuals from the UK Biobank. RESULTS/UNASSIGNED:<0.0001). These results enabled tissue expression prediction of these 988 to 2875 putative BP genes in individuals of both cohorts to construct an expression polygenic score. This score explained ≈27% of the reported single-nucleotide variant heritability, substantially higher than expected from prior studies. CONCLUSIONS/UNASSIGNED:Our work demonstrates the power of tissue-restricted comprehensive CRE analysis, followed by CRE-based expression prediction, for understanding BP regulation in relevant tissues and provides dual-modality supporting evidence, CRE and expression, for the causality genes.
PMID: 38747164
ISSN: 1524-4563
CID: 5668622

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

Lee, Dongwon; Han, Seong Kyu; Yaacov, Or; Berk-Rauch, Hanna; Mathiyalagan, Prabhu; Ganesh, Santhi K; Chakravarti, Aravinda
Genome-wide association studies (GWASs) have identified numerous variants associated with polygenic traits and diseases. However, with few exceptions, a mechanistic understanding of which variants affect which genes in which tissues to modulate trait variation is lacking. Here, we present genomic analyses to explain trait heritability of blood pressure (BP) through the genetics of transcriptional regulation using GWASs, multiomics data from different tissues, and machine learning approaches. Approximately 500,000 predicted regulatory variants across four tissues explain 33.4% of variant heritability: 2.5%, 5.3%, 7.7%, and 11.8% for kidney-, adrenal-, heart-, and artery-specific variants, respectively. Variation in the enhancers involved shows greater tissue specificity than in the genes they regulate, suggesting that gene regulatory networks perturbed by enhancer variants in a tissue relevant to a phenotype are the major source of interindividual variation in BP. Thus, our study provides an approach to scan human tissue and cell types for their physiological contribution to any trait.
PMID: 37910504
ISSN: 2211-1247
CID: 5590312

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

Chatterjee, Sumantra; Fries, Lauren E; Yaacov, Or; Hu, Nan; Berk-Rauch, Hanna E; Chakravarti, Aravinda
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, with an altered transcriptome of 2,382 differentially expressed genes across diverse neuronal and mesenchymal functions. A parsimonious hypothesis for these results is that beyond RET's 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 transcriptome but were unlikely to have had HSCR: thus, genetic or epigenetic changes in addition to those in RET are required for aganglionosis.
PMID: 37948459
ISSN: 1553-7404
CID: 5607952

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

Chatterjee, Sumantra; Fries, Lauren E; Yaacov, Or; Hu, Nan; Berk-Rauch, Hanna E; Chakravarti, Aravinda
ISSN: 2692-8205
CID: 5294112

PARK16 locus: Differential effects of the non-coding rs823114 on Parkinson's disease risk, RNA expression, and DNA methylation [Letter]

Goldstein, Orly; Gana-Weisz, Mali; Casey, Fergal; Meltzer-Fridrich, Hila; Yaacov, Or; Waldman, Yedael Y; Lin, Dongdong; Mordechai, Yael; Zhu, Jing; Cullen, Patrick F; Omer, Nurit; Shiner, Tamara; Thaler, Avner; Bar-Shira, Anat; Mirelman, Anat; John, Sally; Giladi, Nir; Orr-Urtreger, Avi
PMID: 33736926
ISSN: 1673-8527
CID: 5631942

Wnt signaling enhances macrophage responses to IL-4 and promotes resolution of atherosclerosis

Weinstock, Ada; Rahman, Karishma; Yaacov, Or; Nishi, Hitoo; Menon, Prashanthi; Nikain, Cyrus A; Garabedian, Michela L; Pena, Stephanie; Akbar, Naveed; Sansbury, Brian E; Heffron, Sean P; Liu, Jianhua; Marecki, Gregory; Fernandez, Dawn; Brown, Emily J; Ruggles, Kelly V; Ramsey, Stephen; Giannarelli, Chiara; Spite, Matthew; Choudhury, Robin P; Loke, P'ng; Fisher, Edward A
Atherosclerosis is a disease of chronic inflammation. We investigated the roles of the cytokines IL-4 and IL-13, the classical activators of STAT6, in the resolution of atherosclerosis inflammation. Using Il4-/-Il13-/- mice, resolution was impaired, and in control mice, in both progressing and resolving plaques, levels of IL-4 were stably low, and IL-13 was undetectable. This suggested that IL-4 is required for atherosclerosis resolution, but collaborates with other factors. We had observed increased Wnt signaling in macrophages in resolving plaques, and human genetic data from others showed that a loss-of-function Wnt mutation was associated with premature atherosclerosis. We now find an inverse association between activation of Wnt signaling and disease severity in mice and humans. Wnt enhanced the expression of inflammation resolving factors after treatment with plaque-relevant low concentrations of IL-4. Mechanistically, activation of the Wnt pathway following lipid lowering potentiates IL-4 responsiveness in macrophages via a PGE2/STAT3 axis.
PMID: 33720008
ISSN: 2050-084x
CID: 4817422

In search of a genetic explanation for LDLc variability in an FH family: common SNPs and a rare mutation in MTTP explain only part of LDL variability in an FH family

Winther, Michael; Shpitzen, Shoshi; Yaacov, Or; Landau, Jakob; Oren, Limor; Foroozan-Rosenberg, Linda; Lev Cohain, Naama; Schurr, Daniel; Meiner, Vardiela; Szalat, Auryan; Carmi, Shai; Hayden, Michael R; Leitersdorf, Eran; Durst, Ronen
We previously identified a highly consanguineous familial hypercholesterolemia (FH) family demonstrating segregation of the JD Bari mutation in the LDL receptor as well as a putative cholesterol-lowering trait. We aimed to identify genes related to the latter effect. LDL cholesterol (LDLc) values were normalized for FH affectation status, age, and gender. Using genome-wide SNP data, we examined whether known SNPs gleaned from a genome-wide association study could explain the variation observed in LDLc. Four individuals with markedly reduced LDL levels underwent whole exome sequencing. After prioritizing all potential mutations, we identified the most promising candidate genes and tested them for segregation with the lowering trait. We transfected a plasmid carrying the top candidate mutation, microsomal triglyceride transfer protein (MTTP) R634C, into COS-7 cells to test enzymatic activity. The SNP score explained 3% of the observed variability. MTTP R634C showed reduced activity (49.1 nmol/ml) compared with the WT allele (185.8 nmol/ml) (P = 0.0012) and was marginally associated with reduced LDLc in FH patients (P = 0.05). Phenotypic variability in a FH pedigree can only partially be explained by a combination of common SNPs and a rare mutation and a rare variant in the MTTP gene. LDLc variability in FH patients may have nongenetic causes.
PMID: 31387896
ISSN: 1539-7262
CID: 5631932

Tricuspid valve reconfiguration following pulmonary artery banding in patients with congenitally corrected transposition of the great arteries as seen on echocardiography [Meeting Abstract]

Halpern, D G; Nathan, M; Yaacov, O; Marx, G
Background: Tricuspid regurgitation (TR) in patients with congenitally corrected transposition of the great arteries (cc-TGA) has been shown to be a major risk factor for adverse outcomes. Pulmonary arterial banding (PAB) procedure shifts the interventricular septum (IVS) towards the systemic ventricle (SV). We hypothesized that the tenting height (TH) of the tricuspid valve (TV) decreases after PAB as a marker of the improved TV competency. Methods: Clinical and echocardiographic analysis of patients with cc-TGA referred for PAB procedure was performed. TV Measurements included TH, TV annular dimensions, TR degree and sphericity index (SI). TH was measured between the coaptation point and the true TV annular plane or the expected plane such as in Ebstein-like TV. Results: 17 patients (70% males) were referred to PAB surgery at a mean age of 3.15+/-4.2 years. Median interval between pre and postsurgery echoes was 293 (IQR 112,386) days. Overall, PAB resulted in a significant decrease in TH [both true (6.8+/-2.2 to5.6+/-1.6 cm; p=0.03) and expected (8.6+/-3.4 to 7.2+/-3.4 cm; p=0.01)]. In patients with mild and above degree of TR (n=10), PAB resulted in significant decrease in TR (by ~1 grade; p=0.026), SV size (by ~1 class; p=0.02) and increase in SI (3.94+/-1.1 to 4.74+/-1.1; p=0.001) (table/image). TV annular dimensions did not significantly change. Conclusions: By shifting the IVS, PAB elongates the SV, resulting in reconfiguration of the TV and reduction in TH with resultant decrease in the degree of TR in patients with cc-TGA. (Figure presented)
ISSN: 0735-1097
CID: 2093642