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Start Over Author "Orozco LD" Topic gene expression regulation
3 results on '"Orozco LD"'

1. Integration of eQTL and a Single-Cell Atlas in the Human Eye Identifies Causal Genes for Age-Related Macular Degeneration.

Author

Orozco LD, Chen HH, Cox C, Katschke KJ Jr, Arceo R, Espiritu C, Caplazi P, Nghiem SS, Chen YJ, Modrusan Z, Dressen A, Goldstein LD, Clarke C, Bhangale T, Yaspan B, Jeanne M, Townsend MJ, van Lookeren Campagne M, and Hackney JA

Subjects
Aged, Aged, 80 and over, Alleles, Choroid metabolism, Databases, Genetic, Female, Genome-Wide Association Study, Humans, Macular Degeneration genetics, Male, Middle Aged, Polymorphism, Single Nucleotide, Quantitative Trait Loci, RNA-Seq, Risk Factors, Single-Cell Analysis, TRPM Cation Channels genetics, TRPM Cation Channels metabolism, Tetraspanins genetics, Tetraspanins metabolism, Transcriptome genetics, Disease Susceptibility metabolism, Gene Expression Regulation genetics, Macular Degeneration metabolism, Retinal Pigment Epithelium metabolism
Abstract

Age-related macular degeneration (AMD) is a leading cause of vision loss. To better understand disease pathogenesis and identify causal genes in GWAS loci for AMD risk, we present a comprehensive database of human retina and retinal pigment epithelium (RPE). Our database comprises macular and non-macular RNA sequencing (RNA-seq) profiles from 129 donors, a genome-wide expression quantitative trait loci (eQTL) dataset that includes macula-specific retina and RPE/choroid, and single-nucleus RNA-seq (NucSeq) from human retina and RPE with subtype resolution from more than 100,000 cells. Using NucSeq, we find enriched expression of AMD candidate genes in RPE cells. We identify 15 putative causal genes for AMD on the basis of co-localization of genetic association signals for AMD risk and eye eQTL, including the genes TSPAN10 and TRPM1. These results demonstrate the value of our human eye database for elucidating genetic pathways and potential therapeutic targets for ocular diseases., Competing Interests: Declaration of Interests L.D.O., H.-H.C., C. Cox, K.J.K., R.A., C.E., P.C., S.S.N., Y.-J.C., Z.M., A.D., L.D.G., C. Clarke, T.B., B.Y., M.J., M.J.T., M.v.L.C., and J.A.H. were employees of Genentech at the time these studies were carried out., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Published
2020
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2. Effect of natural genetic variation on enhancer selection and function.

Author

Heinz S, Romanoski CE, Benner C, Allison KA, Kaikkonen MU, Orozco LD, and Glass CK

Subjects
Amino Acid Motifs genetics, Animals, Base Sequence, Cell Lineage genetics, DNA-Binding Proteins metabolism, Histones chemistry, Histones metabolism, Macrophages metabolism, Male, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Models, Biological, Mutation genetics, NF-kappa B metabolism, Protein Binding, Reproducibility of Results, Transcription Factor RelA metabolism, Enhancer Elements, Genetic genetics, Gene Expression Regulation genetics, Genetic Variation genetics, Selection, Genetic genetics, Transcription Factors metabolism
Abstract

The mechanisms by which genetic variation affects transcription regulation and phenotypes at the nucleotide level are incompletely understood. Here we use natural genetic variation as an in vivo mutagenesis screen to assess the genome-wide effects of sequence variation on lineage-determining and signal-specific transcription factor binding, epigenomics and transcriptional outcomes in primary macrophages from different mouse strains. We find substantial genetic evidence to support the concept that lineage-determining transcription factors define epigenetic and transcriptomic states by selecting enhancer-like regions in the genome in a collaborative fashion and facilitating binding of signal-dependent factors. This hierarchical model of transcription factor function suggests that limited sets of genomic data for lineage-determining transcription factors and informative histone modifications can be used for the prioritization of disease-associated regulatory variants.

Published
2013
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3. Effect of natural genetic variation on enhancer selection and function

Author

Heinz, S, Romanoski, CE, Benner, C, Allison, KA, Kaikkonen, MU, Orozco, LD, and Glass, CK

Subjects
Male, Enhancer Elements, General Science & Technology, 1.1 Normal biological development and functioning, Amino Acid Motifs, Inbred C57BL, Histones, Mice, Genetic, Underpinning research, Models, Genetics, Animals, 2.1 Biological and endogenous factors, Cell Lineage, Aetiology, Selection, Inbred BALB C, Base Sequence, Macrophages, Human Genome, NF-kappa B, Transcription Factor RelA, Reproducibility of Results, Genetic Variation, Biological, DNA-Binding Proteins, Gene Expression Regulation, Mutation, Generic health relevance, Transcription Factors, Protein Binding, Biotechnology
Abstract

The mechanisms by which genetic variation affects transcription regulation and phenotypes at the nucleotide level are incompletely understood. Here we use natural genetic variation as an in vivo mutagenesis screen to assess the genome-wide effects of sequence variation on lineage-determining and signal-specific transcription factor binding, epigenomics and transcriptional outcomes in primary macrophages from different mouse strains. We find substantial genetic evidence to support the concept that lineage-determining transcription factors define epigenetic and transcriptomic states by selecting enhancer-like regions in the genome in a collaborative fashion and facilitating binding of signal-dependent factors. This hierarchical model of transcription factor function suggests that limited sets of genomic data for lineage-determining transcription factors and informative histone modifications can be used for the prioritization of disease-associated regulatory variants.

Published
2013

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