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; Lucia Carbone

doi:10.1038/s41467-023-43841-8

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

Nat Commun. 2023 Dec 7;14(1):8111. doi: 10.1038/s41467-023-43841-8.

Authors

Mariam Okhovat^#¹, Jake VanCampen^#², Kimberly A Nevonen², Lana Harshman^{3

4}, Weiyu Li^{3

4}, Cora E Layman², Samantha Ward², Jarod Herrera², Jackson Wells², Rory R Sheng^{3

4}, Yafei Mao^{5

6}, Blaise Ndjamen⁷, Ana C Lima⁸, Katinka A Vigh-Conrad⁸, Alexandra M Stendahl⁸, Ran Yang⁸, Lev Fedorov⁹, Ian R Matthews¹⁰, Sarah A Easow¹⁰, Dylan K Chan¹⁰, Taha A Jan¹¹, Evan E Eichler^{5

12}, Sandra Rugonyi¹³, Donald F Conrad^{8

14}, Nadav Ahituv^{15

16}, Lucia Carbone^{17

18

19

20}

Affiliations

¹ Department of Medicine, Knight Cardiovascular Institute, Oregon Health and Science University, Portland, OR, USA. okhovat@ohsu.edu.
² Department of Medicine, Knight Cardiovascular Institute, Oregon Health and Science University, Portland, OR, USA.
³ Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA, USA.
⁴ Institute for Human Genetics, University of California San Francisco, San Francisco, CA, USA.
⁵ Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA, USA.
⁶ Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, China.
⁷ Histology and Light Microscopy Core Facility, Gladstone Institutes, San Francisco, CA, USA.
⁸ Division of Genetics, Oregon National Primate Research Center, Beaverton, OR, USA.
⁹ OHSU Transgenic Mouse Models Core Lab, Oregon Health and Science University, Portland, OR, USA.
¹⁰ Department of Otolaryngology-Head and Neck Surgery, University of California, San Francisco, CA, USA.
¹¹ Department of Otolaryngology-Head and Neck Surgery, Vanderbilt University Medical Center, Nashville, TN, USA.
¹² Howard Hughes Medical Institute, University of Washington, Seattle, WA, 98195, USA.
¹³ Department of Biomedical Engineering, Oregon Health and Science University, Portland, OR, USA.
¹⁴ Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, OR, USA.
¹⁵ Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA, USA. nadav.ahituv@ucsf.edu.
¹⁶ Institute for Human Genetics, University of California San Francisco, San Francisco, CA, USA. nadav.ahituv@ucsf.edu.
¹⁷ Department of Medicine, Knight Cardiovascular Institute, Oregon Health and Science University, Portland, OR, USA. carbone@ohsu.edu.
¹⁸ Division of Genetics, Oregon National Primate Research Center, Beaverton, OR, USA. carbone@ohsu.edu.
¹⁹ Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, OR, USA. carbone@ohsu.edu.
²⁰ Department of Medical Informatics and Clinical Epidemiology, Oregon Health and Science University, Portland, OR, USA. carbone@ohsu.edu.

^# Contributed equally.

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.

MeSH terms

Animals
Chromatin
Chromatin Immunoprecipitation Sequencing
Epigenomics
Gene Expression Regulation
Genome*
Genomics*
Humans
Mammals / genetics
Mice

Substances

Chromatin

Abstract

MeSH terms

Substances

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