A5075153628- Nutrition, Genetics, and Disease
- Adipose Tissue and Metabolism
- Pancreatic function and diabetes
- Pluripotent Stem Cells Research
- Metabolism, Diabetes, and Cancer
- Bioinformatics and Genomic Networks
- Genetic Associations and Epidemiology
- CRISPR and Genetic Engineering
- Diet, Metabolism, and Disease
- RNA Research and Splicing
- Genetic Mapping and Diversity in Plants and Animals
- RNA modifications and cancer
- Genomics and Chromatin Dynamics
- Liver Disease Diagnosis and Treatment
- Congenital heart defects research
- Single-cell and spatial transcriptomics
- Endoplasmic Reticulum Stress and Disease
- Genomics and Phylogenetic Studies
- Genomics and Rare Diseases
- Genetics, Aging, and Longevity in Model Organisms
- Cancer-related molecular mechanisms research
- Epigenetics and DNA Methylation
- 3D Printing in Biomedical Research
- Lipid metabolism and biosynthesis
- Williams Syndrome Research
Cardiovascular Institute of the South
2014-2024
Stanford University
2015-2024
Ikerbasque
2024
BioCruces Health research Institute
2024
University of the Basque Country
2024
Providence College
2021
VA Palo Alto Health Care System
2017
Stanford Medicine
2014
Recent genome wide association studies have identified a number of genes that contribute to the risk for coronary heart disease. One such gene, TCF21, encodes basic-helix-loop-helix transcription factor believed serve critical role in development epicardial progenitor cells give rise artery smooth muscle (SMC) and cardiac fibroblasts. Using reporter gene immunolocalization with mouse human tissues we found vascular TCF21 expression adult is restricted primarily adventitial associated...
Abstract Structural variants (SVs) and short tandem repeats (STRs) comprise a broad group of diverse DNA which vastly differ in their sizes distributions across the genome. Here, we identify genomic features SV classes STRs that are associated with gene expression complex traits, including locations relative to eGenes, likelihood being multiple eGene types (e.g., coding, noncoding, level evolutionary constraint), effect sizes, linkage disequilibrium tagging single nucleotide used GWAS, GWAS...
Both environmental factors and genetic loci have been associated with coronary artery disease (CAD), however gene-gene gene-environment interactions that might identify molecular mechanisms of risk are not easily studied by human approaches. We previously identified the transcription factor TCF21 as causal CAD gene at 6q23.2 characterized its downstream transcriptional network is enriched for GWAS genes. Here we investigate hypothesis interacts a target gene, aryl hydrocarbon receptor (AHR),...
Abstract Although marrow adipocytes and osteoblasts derive from a common bone stromal cells (BMSCs), the mechanisms that underlie osteoporosis-associated loss adipogenesis during prolonged steroid treatment are unclear. We show in human BMSCs (hBMSCs) glucocorticoid receptor (GR) signaling response to high concentrations of (GC) supports but inhibits osteogenesis by reducing c-Jun expression hBMSC proliferation. Conversely, significantly lower GC, which permit proliferation, necessary for...
Abstract Genetic variation in the FAM13A (Family with Sequence Similarity 13 Member A) locus has been associated several glycemic and metabolic traits genome-wide association studies (GWAS). Here, we demonstrate that humans, alleles are increased expression subcutaneous adipose tissue (SAT) an insulin resistance-related phenotype (e.g. higher waist-to-hip ratio fasting levels, but lower body fat). In human adipocyte models, knockdown of preadipocytes accelerates differentiation. mice, Fam13a...
Insulin resistance is present in one-quarter of the general population, predisposing these people to a wide range diseases. Our aim was identify cell-intrinsic determinants insulin this population using induced pluripotent stem cell–derived (iPSC–derived) myoblasts (iMyos). We found that cells exhibited large network altered protein phosphorylation vitro. Integrating data with from type 2 diabetic iMyos revealed critical sites conserved IRS-1, AKT, mTOR, and TBC1D1 addition changes involved...
We recently identified human N-acetyltransferase 2 (NAT2) as an insulin resistance (IR) gene. Here, we examine the cellular mechanism linking NAT2 to IR and find that Nat1 (mouse ortholog of NAT2) is co-regulated with key mitochondrial genes. RNAi-mediated silencing led dysfunction characterized by increased intracellular reactive oxygen species fragmentation well decreased membrane potential, biogenesis, mass, respiration, ATP generation. These effects were consistent in 3T3-L1 adipocytes,...
Structural variants (SVs) and short tandem repeats (STRs) are important sources of genetic diversity but not routinely analyzed in studies because they difficult to accurately identify genotype. Because SVs STRs range size type, it is necessary apply multiple algorithms that incorporate different types evidence from sequencing data employ complex filtering strategies discover a comprehensive set high-quality reproducible variants. Here we assemble 719 deep whole genome (WGS) samples (mean...
Abstract Background Identification of causal genes for polygenic human diseases has been extremely challenging, and our understanding how physiological pharmacological stimuli modulate genetic risk at disease-associated loci is limited. Specifically, insulin resistance (IR), a common feature cardiometabolic disease, including type 2 diabetes, obesity, dyslipidemia, lacks well-powered genome-wide association studies (GWAS), therefore, few associated have identified. Methods Here, we perform...
Abstract Genetic predisposition and unhealthy lifestyle are risk factors for nonalcoholic fatty liver disease (NAFLD). We investigated whether the genetic of NAFLD is modified by physical activity, muscular fitness, and/or adiposity. In up to 242,524 UK Biobank participants without excessive alcohol intake or known disease, we examined cross‐sectional interactions joint associations body mass index (BMI), a score (GRS) with alanine aminotransferase (ALT) levels proxy definition suspected ALT...
Insulin resistance (IR) precedes the development of type 2 diabetes (T2D) and increases cardiovascular disease risk. Although genome wide association studies (GWAS) have uncovered new loci associated with T2D, their contribution to explain mechanisms leading decreased insulin sensitivity has been very limited. Thus, approaches are necessary explore genetic architecture resistance. To that end, we generated an iPSC library across spectrum in humans. RNA-seq based analysis 310 induced...
TCF21 is a basic helix–loop–helix transcription factor that has recently been implicated as contributing to susceptibility coronary heart disease based on genome wide association studies. In order identify transcriptionally regulated target genes in major relevant cell type, we performed siRNA knockdown of vitro cultured human artery smooth muscle cells and compared the transcriptome siTCF21 versus siCONTROL treated cells. The raw (FASTQ) well processed (BED) data from 3 technical replicates...
Abstract Identifying regulatory genetic effects in pluripotent cells provides important insights into disease variants with potentially transient or developmental origins. Combining existing and newly-generated data, we characterized 1,367 iPSC lines from 948 unique donors, collectively analyzed within the “Integrated QTL” (i2QTL) Consortium. The sample size of our study allowed us to derive most comprehensive map quantitative trait loci (QTL) human date. We mapped nearby common on five...
Human induced pluripotent stem cell (hiPSC) lines have previously been generated through the NHLBI sponsored NextGen program at nine individual study sites. Here, we examined structural integrity of 506 hiPSC as determined by copy number variations (CNVs). We observed that 149 acquired 258 CNVs relative to donor DNA. identified six recurrent regions on chromosomes 1, 2, 3, 16 and 20 overlapped with cancer associated genes. Furthermore, genes mapping show an enrichment in related biological...
CROP-Seq combines gene silencing using CRISPR interference with single-cell RNA sequencing. Here, we applied to study adipogenesis and adipocyte biology. Human preadipocyte SGBS cell line expressing KRAB-dCas9 was transduced a sgRNA library. Following selection, individual cells were captured microfluidics at different timepoints during adipogenesis. Bioinformatic analysis of transcriptomic data used determine the knockdown effects, dysregulated pathways, predict cellular phenotypes....
Metabolic dysfunction-associated fatty liver disease (MASLD) is the most prevalent chronic pathology in western countries, with serious public health consequences. Efforts to identify causal genes for MASLD have been hampered by relative paucity of human data from gold standard magnetic resonance quantification hepatic fat. To overcome insufficient sample size, genome-wide association studies using surrogate phenotypes used, but only a small number loci identified date. In this study, we...