title: Multimodal Regulation Orchestrates Normal and Complex Disease States in the Retina.
abstract: Regulation of biological processes occurs through complex, synergistic mechanisms. In this study, we discovered the synergistic orchestration of multiple mechanisms regulating the normal and diseased state (age related macular degeneration, AMD) in the retina. We uncovered gene networks with overlapping feedback loops that are modulated by nuclear hormone receptors (NHR), miRNAs, and epigenetic factors. We utilized a comprehensive filtering and pathway analysis strategy comparing miRNA and microarray data between three mouse models and human donor eyes (normal and AMD). The mouse models lack key NHRS (Nr2e3, RORA) or epigenetic (Ezh2) factors. Fifty-four total miRNAs were differentially expressed, potentially targeting over 150 genes in 18 major representative networks including angiogenesis, metabolism, and immunity. We identified sixty-eight genes and 5 miRNAS directly regulated by NR2E3 and/or RORA. After a comprehensive analysis, we discovered multimodal regulation by miRNA, NHRs, and epigenetic factors of three miRNAs (miR-466, miR1187, and miR-710) and two genes (Ell2 and Entpd1) that are also associated with AMD. These studies provide insight into the complex, dynamic modulation of gene networks as well as their impact on human disease, and provide novel data for the development of innovative and more effective therapeutics.
authors.affiliation: Schepens Eye Research Institute, Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston, MA, United States of America.
authors.forename: A M
authors.initials: AM
authors.lastname: Olivares
authors.affiliation: Genetics, Cell Biology, and Anatomy, University of Nebraska Medical Center, Omaha, Nebraska, United States of America.
authors.forename: A S
authors.initials: AS
authors.lastname: Jelcick
authors.affiliation: Genetics, Cell Biology, and Anatomy, University of Nebraska Medical Center, Omaha, Nebraska, United States of America.
authors.forename: J
authors.initials: J
authors.lastname: Reinecke
authors.affiliation: Genetics, Cell Biology, and Anatomy, University of Nebraska Medical Center, Omaha, Nebraska, United States of America.
authors.forename: B
authors.initials: B
authors.lastname: Leehy
authors.affiliation: Schepens Eye Research Institute, Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston, MA, United States of America.
authors.forename: A
authors.initials: A
authors.lastname: Haider
authors.affiliation: Ophthalmology and Visual Sciences, John A. Moran Eye Center, University of Utah School of Medicine, Salt Lake City, Utah, United States of America.
authors.forename: M A
authors.initials: MA
authors.lastname: Morrison
authors.affiliation: Schepens Eye Research Institute, Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston, MA, United States of America.
authors.forename: L
authors.initials: L
authors.lastname: Cheng
authors.affiliation: Schepens Eye Research Institute, Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston, MA, United States of America.
authors.forename: D F
authors.initials: DF
authors.lastname: Chen
authors.affiliation: Ophthalmology and Visual Sciences, John A. Moran Eye Center, University of Utah School of Medicine, Salt Lake City, Utah, United States of America.
authors.forename: M M
authors.initials: MM
authors.lastname: DeAngelis
authors.affiliation: Schepens Eye Research Institute, Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston, MA, United States of America. neena_haider@meei.harvard.edu.
authors.forename: N B
authors.initials: NB
authors.lastname: Haider
mesh_terms: D015415:Biomarkers; D018450:Disease Progression; D004198:Disease Susceptibility; D044127:Epigenesis, Genetic; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D006801:Humans; D008268:Macular Degeneration / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D035683:MicroRNAs / Q000235:genetics; D008954:Models, Biological; D034622:RNA Interference; D012333:RNA, Messenger / Q000235:genetics; D012160:Retina / Q000378:metabolism* / Q000473:pathology; D012164:Retinal Diseases / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction
chemical_list: D015415:Biomarkers; D035683:MicroRNAs; D012333:RNA, Messenger