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2023 ACMG Annual Clinical Genetics Meeting Digital ...
Interrogating the pathologic noncoding genome with ...
Interrogating the pathologic noncoding genome with tissue-specific multiomics
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Pdf Summary
This study focuses on investigating the transcriptional regulatory landscape of developing human retinal pigment epithelium (RPE) using an in vitro model system. The researchers used human induced pluripotent stem cells (hiPSC) to differentiate into mature RPE and generated RNA-seq and ATAC-seq data from single cells and bulk populations at eight differentiation timepoints. Integrated analysis of the chromatin accessibility and transcriptome profiles revealed the dynamics of the regulatory landscape during RPE differentiation and identified RPE-specific interactions between distal cis-regulatory elements and target genes.<br /><br />The results confirmed that hiPSC differentiation to RPE fate follows the known neuroectodermal lineage and replicates primary fetal RPE transcriptional signatures. The 3D chromatin contact profiling supported the changing regulatory landscape of RPE differentiation and uncovered interactions of cis-regulatory elements with their target genes, including developmental and disease-associated loci.<br /><br />The study also conducted a transcription factor-focused analysis, predicting a gene regulatory network controlling RPE specification and maturation. Known and novel disease-relevant regulatory elements were identified for known developmental and retinal disease-related genes. Additionally, the researchers performed genome sequencing of an unsolved inherited retinal dystrophy (IRD) cohort and identified a novel noncoding variant upstream of MFRP that disrupts a consensus OTX2 binding site, which may explain the IRD and nanophthalmos phenotype in the patient.<br /><br />Overall, this comprehensive chromatin and transcriptome atlas of hiPSC-RPE differentiation provides a genome regulatory map for evaluating normal and pathogenic chromatin dynamics and transcriptional regulation in human RPE development and disease. By establishing this regulatory map, it reduces the search space for noncoding variants in IRDs and other RPE-associated phenotypes, providing insights into the molecular mechanisms underlying retinal diseases.
Asset Subtitle
Presenting Author - Robert B. Hufnagel, MD, PhD; Co-Author - David McGaughey, PhD; Co-Author - Ameera Mungale, BS; Co-Author - Koray D. Kaya, PhD; Co-Author - Bin Guan, PhD, FACMG; Co-Author - Michelle Brinkmeier, MS; Co-Author - Lev Prasov, MD, PhD; Co-Author - Temesgen D. Fufa, PhD;
Meta Tag
Bioinformatics
Differentiation
Epigenetics
Eye disorders
Genetic Testing
Genome sequencing
Genomic Methodologies
Genomic Structure
NextGen Sequencing
Variant Detection
Visual System
Co-Author
David McGaughey, PhD
Co-Author
Ameera Mungale, BS
Co-Author
Koray D. Kaya, PhD
Co-Author
Bin Guan, PhD, FACMG
Co-Author
Michelle Brinkmeier, MS
Co-Author
Lev Prasov, MD, PhD
Co-Author
Temesgen D. Fufa, PhD
Presenting Author
Robert B. Hufnagel, MD, PhD
Keywords
transcriptional regulatory landscape
retinal pigment epithelium
in vitro model
stem cells
RNA-seq
ATAC-seq
chromatin accessibility
cis-regulatory elements
gene regulatory network
retinal diseases
© 2025 American College of Medical Genetics and Genomics. All rights reserved.
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