Alexias Safi
A5026071922- Genomics and Chromatin Dynamics
- RNA Research and Splicing
- Epigenetics and DNA Methylation
- RNA and protein synthesis mechanisms
- RNA modifications and cancer
- Chromosomal and Genetic Variations
- Genetic Associations and Epidemiology
- CRISPR and Genetic Engineering
- Genetic Mapping and Diversity in Plants and Animals
- Cancer-related molecular mechanisms research
- Genomic variations and chromosomal abnormalities
- Estrogen and related hormone effects
- Congenital heart defects research
- NF-κB Signaling Pathways
- Cancer-related Molecular Pathways
- Genetic and phenotypic traits in livestock
- Single-cell and spatial transcriptomics
- Advanced biosensing and bioanalysis techniques
- Gene expression and cancer classification
- Fungal and yeast genetics research
- Adipose Tissue and Metabolism
- Cancer Genomics and Diagnostics
- MicroRNA in disease regulation
- Microtubule and mitosis dynamics
- DNA Repair Mechanisms
Duke University
2012-2022
Duke University Hospital
2003-2022
Duke Medical Center
2003-2022
Center for Human Genetics
2019
Center for Genomic Science
2019
DNase I hypersensitive sites (DHSs) are markers of regulatory DNA and have underpinned the discovery all classes cis-regulatory elements including enhancers, promoters, insulators, silencers locus control regions. Here we present first extensive map human DHSs identified through genome-wide profiling in 125 diverse cell tissue types. We identify ∼2.9 million that encompass virtually known experimentally validated sequences expose a vast trove novel elements, most with highly cell-selective...
Most genetic risk for psychiatric disease lies in regulatory regions, implicating pathogenic dysregulation of gene expression and splicing. However, comprehensive assessments transcriptomic organization diseased brains are limited. In this work, we integrated genotypes RNA sequencing brain samples from 1695 individuals with autism spectrum disorder (ASD), schizophrenia, bipolar disorder, as well controls. More than 25% the transcriptome exhibits differential splicing or expression,...
Despite progress in defining genetic risk for psychiatric disorders, their molecular mechanisms remain elusive. Addressing this, the PsychENCODE Consortium has generated a comprehensive online resource adult brain across 1866 individuals. The contains ~79,000 brain-active enhancers, sets of Hi-C linkages, and topologically associating domains; single-cell expression profiles many cell types; quantitative-trait loci (QTLs); further QTLs associated with chromatin, splicing, cell-type...
INTRODUCTION The brain is responsible for cognition, behavior, and much of what makes us uniquely human. development the a highly complex process, this process reliant on precise regulation molecular cellular events grounded in spatiotemporal transcriptome. Disruption can lead to neuropsychiatric disorders. RATIONALE regulatory, epigenomic, transcriptomic features human have not been comprehensively compiled across time, regions, or cell types. Understanding etiology disorders requires...
Genes implicated in neuropsychiatric disorders are active human fetal brain, yet difficult to study a longitudinal fashion. We demonstrate that organoids from pluripotent cells model cerebral cortical development on the molecular level before 16 weeks postconception. A multiomics analysis revealed differentially genes and enhancers, with greatest changes occurring at transition stem progenitors. Networks of converging gene enhancer modules were assembled into six four global patterns...
Regulatory elements recruit transcription factors that modulate gene expression distinctly across cell types, but the relationships among these remains elusive. To address this, we analyzed matched DNase-seq and data for 112 human samples representing 72 types. We first defined more than 1800 clusters of DNase I hypersensitive sites (DHSs) with similar tissue specificity signal patterns. then used to uncover distinct associations between DHSs promoters, CpG islands, conserved elements,...
Schizophrenia genome-wide association studies have identified >150 regions of the genome associated with disease risk, yet there is little evidence that coding mutations contribute to this disorder. To explore mechanism non-coding regulatory elements in schizophrenia, we performed ATAC-seq on adult prefrontal cortex brain samples from 135 individuals schizophrenia and 137 controls, 118,152 peaks. These accessible chromatin are highly enriched for SNP heritability. Accessible overlap...
Genome engineering technologies based on the CRISPR/Cas9 and TALE systems are enabling new approaches in science biotechnology. However, specificity of these tools complex genomes role chromatin structure determining DNA binding not well understood. We analyzed genome-wide effects TALE- CRISPR-based transcriptional activators human cells using ChIP-seq to assess DNA-binding RNA-seq measure perturbing transcriptome. Additionally, DNase-seq was used remodeling that occurs as a result their...
Glucocorticoids are potent steroid hormones that regulate immunity and metabolism by activating the transcription factor (TF) activity of glucocorticoid receptor (GR). Previous models have proposed DNA binding motifs sites chromatin accessibility predetermine GR activity. However, there vast excesses both features relative to number sites. Thus, these alone unlikely account for specificity To identify genomic epigenetic contributions downstream changes resultant from binding, we performed...
Cellular heterogeneity in the human brain obscures identification of robust cellular regulatory networks, which is necessary to understand function non-coding elements and impact genetic variation. Here we integrate genome-wide chromosome conformation data from purified neurons glia with transcriptomic enhancer profiles, characterize gene landscape two major cell classes brain. We then leverage cell-type-specific landscapes gain insight into etiology several disorders. find that Alzheimer's...
Exfoliation syndrome (XFS) is a common, age-related, systemic fibrillinopathy. It greatly increases risk of exfoliation glaucoma (XFG), major worldwide cause irreversible blindness. Coding variants in the lysyl oxidase-like 1 (LOXL1) gene are strongly associated with XFS all studied populations, but functional role for these has not been established. To identify additional candidate variants, we sequenced entire LOXL1 genomic locus (∼40 kb) 50 indigenous, black South African cases and...
Cellular stresses activate the tumor suppressor p53 protein leading to selective binding DNA response elements (REs) and gene transactivation from a large pool of potential REs (p53REs). To elucidate how p53RE sequences local chromatin context interact affect transactivation, we mapped genome-wide localizations H3K4me3 in untreated doxorubicin (DXR)-treated human lymphoblastoid cells. We examined relationships among occupancy, expression, H3K4me3, accessibility (DNase 1 hypersensitivity,...
Higher order chromatin structure establishes domains that organize the genome and coordinate gene expression. However, molecular mechanisms controlling transcription of individual loci within a topological domain (TAD) are not fully understood. The cystic fibrosis transmembrane conductance regulator (CFTR) provides paradigm for investigating these mechanisms. CFTR occupies TAD bordered by CTCF/cohesin binding sites which cell-type-selective cis-regulatory elements locus. We showed previously...
Gene transcription profiles across tissues are largely defined by the activity of regulatory elements, most which correspond to regions accessible chromatin. Regulatory element is in turn modulated genetic variation, resulting variable rates individuals. The interplay these factors, however, poorly understood. Here we characterize expression and chromatin state dynamics three tissues—liver, lung, kidney—in 47 strains Collaborative Cross (CC) mouse population, examining regulation...
ABSTRACT The epicardium is a mesothelial tissue layer that envelops the heart. Cardiac injury activates dynamic gene expression programs in epicardial tissue, which zebrafish enables subsequent regeneration through paracrine and vascularizing effects. To identify enhancer elements (TREEs) control injury-induced during heart regeneration, we profiled transcriptomes chromatin accessibility cells purified from regenerating hearts. We identified hundreds of candidate TREEs, are defined by...