An integrative TAD catalog in lymphoblastoid cell lines discloses the functional impact of deletions and insertions in human genomes.
Document Type
Article
Publication Date
12-23-2024
Original Citation
Li C,
Bonder M,
Syed S,
Jensen M,
,
,
Gerstein M,
Zody M,
Chaisson M,
Talkowski M,
Marschall T,
Korbel J,
Eichler E,
Lee C,
Shi X.
An integrative TAD catalog in lymphoblastoid cell lines discloses the functional impact of deletions and insertions in human genomes. Genome Res. 2024;34(12):2304-18.
Keywords
JGM, Humans, Genome, Human, Cell Line, Chromatin, Mutagenesis, Insertional, Gene Expression Regulation
JAX Source
Genome Res. 2024;34(12):2304-18.
ISSN
1549-5469
PMID
39638559
DOI
https://doi.org/10.1101/gr.279419.124
Grant
This work was supported by the National Insti- tutes of Health (NIH) grants U24HG007497 (to C.Lee, E.E.E., J.O.K., T.M., M.B.G., and X.S.), R01HG002385 and R01HG 010169 (to E.E.E.), and MH115957 (to M.E.T.); the German Hu- man Genome-Phenome Archive (DFG [NFDI 1/1] to J.O.K.); the European Research Council (ERC Consolidator grant 773026 to J.O.K.).
Abstract
The human genome is packaged within a three-dimensional (3D) nucleus and organized into structural units known as com- partments, topologically associating domains (TADs), and loops. TAD boundaries, separating adjacent TADs, have been found to be well conserved across mammalian species and more evolutionarily constrained than TADs themselves. Recent studies show that structural variants (SVs) can modify 3D genomes through the disruption of TADs, which play an essential role in insulating genes from outside regulatory elements’ aberrant regulation. However, how SV affects the 3D genome structure and their association among different aspects of gene regulation and candidate cis-regulatory elements (cCREs) have rarely been studied systematically. Here, we assess the impact of SVs intersecting with TAD boundaries by developing an integrative Hi-C analysis pipeline, which enables the generation of an in-depth catalog of TADs and TAD boundaries in human lymphoblastoid cell lines (LCLs) to fill the gap of limited resources. Our catalog contains 18,865 TADs, including 4596 sub-TADs, with 185 SVs (TAD–SVs) that alter chromatin architecture. By leveraging the ENCODE registry of cCREs in humans, we determine that 34 of 185 TAD–SVs intersect with cCREs and observe significant enrichment of TAD–SVs within cCREs. This study provides a database of TADs and TAD–SVs in the human genome that will facilitate future investigations of the impact of SVs on chromatin structure and gene regulation in health and disease.
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.