TAD evolutionary and functional characterization reveals diversity in mammalian TAD boundary properties and function
Year: 2023
Type: article
Abstract: Topological associating domains (TADs) are self-interacting genomic units crucial for shaping gene regulation patterns. Despite their importance, the extent of their evolutionary conservation and its functional implications remain largely unknown. In this study, we generate Hi-C and ChIP-seq data and compare TAD organization across four primate and four rodent species and characterize the genetic and epigenetic properties of TAD boundaries in correspondence to their evolutionary conservation. We find 14% of all human TAD boundaries to be shared among all eight species (ultraconserved), while 15% are human-specific. Ultraconserved TAD boundaries have stronger insulation strength, CTCF binding, and enrichment of older retrotransposons compared to species-specific boundaries. CRISPR-Cas9 knockouts of an ultraconserved boundary in a mouse model lead to tissue-specific gene expression changes and morphological phenotypes. Deletion of a human-specific boundary near the autism-related AUTS2 gene results in the upregulation of this gene in neurons. Overall, our study provides pertinent TAD boundary evolutionary conservation annotations and showcases the functional importance of TAD evolution.
Source: Nature Communications
Authors: Mariam Okhovat, Jake VanCampen, Kimberly A. Nevonen, Lana Harshman, Weiyu Li, Cora E. Layman, Samantha Ward, Jarod Herrera, Jackson Wells, Rory R. Sheng, Yafei Mao, Blaise Ndjamen, Ana C. Lima, Katinka A. Vigh-Conrad, Alexandra M. Stendahl, Ran Yang, Lev Fedorov, Ian R. Matthews, Sarah A. Easow, Dylan K. Chan, Taha A. Jan, Evan E. Eichler, Sandra Rugonyi, Donald F. Conrad, Nadav Ahituv, Lucia Carbone
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $6,290
Funders: Howard Hughes Medical Institute, U.S. Department of Health and Human Services, Oregon Health and Science University, University of Oregon, National Institutes of Health, Centers for Disease Control and Prevention, Oregon National Primate Research Center, National Human Genome Research Institute, NIH Office of the Director, National Institute on Deafness and Other Communication Disorders, Eunice Kennedy Shriver National Institute of Child Health and Human Development
Awards: G104308456, G1294778923, G1623837652, G1846172760, Comparative and functional analysis of conservation and rearrangement of topologically associating domains across mammals., G4271287713, Automated Slide Scanner with Brightfield and Fluorescence for Stereology, FISH and Brain Connectivity Mapping, G5992890995, G6189743142, G6371209607, G9000046723, Genomics of spermatogenic impairment, Long-read sequence and assembly of segmental duplications, Massively parallel characterization of variants and elements impacting transcriptional regulation in dynamic cellular systems, Single cell analysis of mitotic regeneration in the mouse vestibular system, Support for National Primate Research Center, Multispecies NHP dGTEx Research Center
OpenAlex ID: W4389428478