TAD evolutionary and functional characterization reveals diversity in mammalian TAD boundary properties and function

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 () and Lucia Carbone ()
Additional contact information
Mariam Okhovat: Oregon Health and Science University
Jake VanCampen: Oregon Health and Science University
Kimberly A. Nevonen: Oregon Health and Science University
Lana Harshman: University of California San Francisco
Weiyu Li: University of California San Francisco
Cora E. Layman: Oregon Health and Science University
Samantha Ward: Oregon Health and Science University
Jarod Herrera: Oregon Health and Science University
Jackson Wells: Oregon Health and Science University
Rory R. Sheng: University of California San Francisco
Yafei Mao: University of Washington School of Medicine
Blaise Ndjamen: Histology and Light Microscopy Core Facility, Gladstone Institutes
Ana C. Lima: Division of Genetics, Oregon National Primate Research Center
Katinka A. Vigh-Conrad: Division of Genetics, Oregon National Primate Research Center
Alexandra M. Stendahl: Division of Genetics, Oregon National Primate Research Center
Ran Yang: Division of Genetics, Oregon National Primate Research Center
Lev Fedorov: Oregon Health and Science University
Ian R. Matthews: University of California
Sarah A. Easow: University of California
Dylan K. Chan: University of California
Taha A. Jan: Vanderbilt University Medical Center
Evan E. Eichler: University of Washington School of Medicine
Sandra Rugonyi: Oregon Health and Science University
Donald F. Conrad: Division of Genetics, Oregon National Primate Research Center
Nadav Ahituv: University of California San Francisco
Lucia Carbone: Oregon Health and Science University

Nature Communications, 2023, vol. 14, issue 1, 1-13

Abstract: 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.

Date: 2023
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-43841-8

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DOI: 10.1038/s41467-023-43841-8

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