Background: Understanding the genetic causes for variability in chromatin accessibility can shed light on the molecular mechanisms through which genetic variants may affect complex traits. Thousands of ATAC-seq samples have been collected that hold information about chromatin accessibility across diverse cell types and contexts, but most of these are not paired with genetic information and come from diverse distinct projects and laboratories.
Results: We report here joint genotyping, chromatin accessibility peak calling, and discovery of quantitative trait loci which influence chromatin accessibility (caQTLs), demonstrating the capability of performing caQTL analysis on a large scale in a diverse sample set without pre-existing genotype information.
Many tissue-specific adult stem cell lineages maintain a balance between proliferation and differentiation. Here, we study how the H3K4me3 methyltransferase Set1 regulates early-stage male germ cells in Drosophila. Early-stage germline-specific knockdown of Set1 results in temporally progressive defects, arising as germ cell loss and developing into overpopulated early-stage germ cells.
View Article and Find Full Text PDFAneuploidy is nearly ubiquitous in tumor genomes, but the role of aneuploidy in the early stages of cancer evolution remains unclear. Here, by inducing heterogeneous aneuploidy in non-transformed human colon organoids (colonoids), we investigated how the effects of aneuploidy on cell growth and differentiation may promote malignant transformation. Previous work implicated p53 activation as a downstream response to aneuploidy induction.
View Article and Find Full Text PDFParkinson's disease (PD) is a progressive neurodegenerative disease characterized by mitochondrial dysfunction and accumulation of alpha-synuclein (α-Syn)-containing protein aggregates known as Lewy bodies (LB). Here, we investigated the entry of α-Syn into mitochondria to cause mitochondrial dysfunction and loss of cellular fitness in vivo. We show that α-Syn expressed in yeast and human cells is constitutively imported into mitochondria.
View Article and Find Full Text PDFBackground: There is interest in identifying novel filtration markers that lead to more accurate GFR estimates than current markers (creatinine and cystatin C) and are more consistent across demographic groups. We hypothesize that large-scale metabolomics can identify serum metabolites that are strongly influenced by glomerular filtration rate (GFR) and are more consistent across demographic variables than creatinine, which would be promising filtration markers for future investigation.
Methods: We evaluated the consistency of associations between measured GFR (mGFR) and 887 common, known metabolites quantified by an untargeted chromatography- and spectroscopy-based metabolomics platform (Metabolon) performed on frozen blood samples from 580 participants in Chronic Kidney Disease in Children (CKiD), 674 participants in Modification of Diet in Renal Disease (MDRD) Study and 962 participants in African American Study of Kidney Disease and Hypertension (AASK).
Many cell types come from tissue-specific adult stem cells that maintain the balance between proliferation and differentiation. Here, we study how the H3K4me3 methyltransferase, Set1, regulates early-stage male germ cell proliferation and differentiation in . Early-stage germline-specific knockdown of results in a temporally progressed defects, arising as germ cell loss and developing to overpopulated early-stage germ cells.
View Article and Find Full Text PDFPopulation-based association studies have identified many genetic risk loci for coronary artery disease (CAD), but it is often unclear how genes within these loci are linked to CAD. Here, we perform interaction proteomics for 11 CAD-risk genes to map their protein-protein interactions (PPIs) in human vascular cells and elucidate their roles in CAD. The resulting PPI networks contain interactions that are outside of known biology in the vasculature and are enriched for genes involved in immunity-related and arterial-wall-specific mechanisms.
View Article and Find Full Text PDFAneuploidy, a near ubiquitous genetic feature of tumors, is a context-dependent driver of cancer evolution; however, the mechanistic basis of this role remains unclear. Here, by inducing heterogeneous aneuploidy in non-transformed human colon organoids (colonoids), we investigate how the effects of aneuploidy on cell growth and differentiation may promote malignant transformation. Single-cell RNA sequencing reveals that the gene expression signature across over 100 unique aneuploid karyotypes is enriched with p53 responsive genes.
View Article and Find Full Text PDFBioinformatics
September 2023
Motivation: Single-cell sequencing technology has become a routine in studying many biological problems. A core step of analyzing single-cell data is the assignment of cell clusters to specific cell types. Reference-based methods are proposed for predicting cell types for single-cell clusters.
View Article and Find Full Text PDFGenome-wide association studies (GWASs) are a valuable tool for understanding the biology of complex human traits and diseases, but associated variants rarely point directly to causal genes. In the present study, we introduce a new method, polygenic priority score (PoPS), that learns trait-relevant gene features, such as cell-type-specific expression, to prioritize genes at GWAS loci. Using a large evaluation set of genes with fine-mapped coding variants, we show that PoPS and the closest gene individually outperform other gene prioritization methods, but observe the best overall performance by combining PoPS with orthogonal methods.
View Article and Find Full Text PDFiScience
May 2023
Genetics have nominated many schizophrenia risk genes and identified convergent signals between schizophrenia and neurodevelopmental disorders. However, functional interpretation of the nominated genes in the relevant brain cell types is often lacking. We executed interaction proteomics for six schizophrenia risk genes that have also been implicated in neurodevelopment in human induced cortical neurons.
View Article and Find Full Text PDFThe impact of genome organization on the control of gene expression persists as a major challenge in regulatory biology. Most efforts have focused on the role of CTCF-enriched boundary elements and TADs, which enable long-range DNA-DNA associations via loop extrusion processes. However, there is increasing evidence for long-range chromatin loops between promoters and distal enhancers formed through specific DNA sequences, including tethering elements, which bind the GAGA-associated factor (GAF).
View Article and Find Full Text PDFBRAF mutations are a significant driver of disease in pediatric low-grade glioma, but the implications of BRAF alterations on the clinical course and treatment response in adult glioma remain unclear. Here, we characterize a multi-institutional cohort of more than 300 patients (>200 adults) with BRAF-mutated glioma using clinical, pathological/molecular, and outcome data. We observed that adult and pediatric BRAF-mutant gliomas harbor distinct clinical and molecular features, with a higher prevalence of BRAF (Class I) and BRAF fusions in pediatric tumors.
View Article and Find Full Text PDFHow pioneer factors interface with chromatin to promote accessibility for transcription control is poorly understood in vivo. Here, we directly visualize chromatin association by the prototypical GAGA pioneer factor (GAF) in live Drosophila hemocytes. Single-particle tracking reveals that most GAF is chromatin bound, with a stable-binding fraction showing nucleosome-like confinement residing on chromatin for more than 2 min, far longer than the dynamic range of most transcription factors.
View Article and Find Full Text PDFBackground: Asian American (AsAm) representation is lacking in conversations surrounding cultural humility in healthcare. We aimed to investigate US medical student perspectives on AsAm patient inclusion in cultural humility training in medical education.
Methods: This qualitative study analyzed free-text responses to an optional, open-ended question presented at the conclusion of an online survey assessing medical student experiences with and perceptions regarding AsAm patients in their medical education.
COVID-19 pathogenesis is associated with an exuberant inflammatory response. However, the tissue injury pattern and immune response in solid-organ transplant recipients (SOTRs) taking immunosuppressive therapy have not been well characterized. Here, we perform both cfDNA and cytokine profiling on plasma samples to map tissue damage, including allograft injury and delineate underlying immunopathology.
View Article and Find Full Text PDFThe SpineJack implant system was recently FDA approved for treatment of vertebral compression fractures (VCF), however United States-based outcomes data is lacking. We sought to examine the safety and clinical outcomes following vertebral augmentation using the SpineJack implant for treatment of VCF in a U.S.
View Article and Find Full Text PDFAlthough much is known about the gene mutations required to drive colorectal cancer (CRC) initiation, the tissue-specific selective microenvironments in which neoplasia arises remains less characterized. Here, we determined whether modulation of intestinal stem cell niche morphogens alone can exert a neoplasia-relevant selective pressure on normal colonic epithelium. Using adult stem cell-derived murine colonic epithelial organoids (colonoids), we employed a strategy of sustained withdrawal of epidermal growth factor (EGF) and epidermal growth factor receptor (EGFR) inhibition to select for and expand survivors.
View Article and Find Full Text PDFBackground: Asian Americans (AsAm) are a rapidly growing population in the U.S. With this growing population, U.
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