Identifying synergistic high-order 3D chromatin conformations from genome-scale nanopore concatemer sequencing.

Autor: Deshpande AS; Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA.; New York Genome Center, New York, NY, USA.; Tri-Institutional PhD Program in Computational Biology and Medicine, New York, NY, USA., Ulahannan N; Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA.; New York Genome Center, New York, NY, USA., Pendleton M; Oxford Nanopore Technologies, New York, NY, USA., Dai X; Oxford Nanopore Technologies, New York, NY, USA., Ly L; Oxford Nanopore Technologies, San Francisco, CA, USA., Behr JM; Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA.; New York Genome Center, New York, NY, USA.; Tri-Institutional PhD Program in Computational Biology and Medicine, New York, NY, USA., Schwenk S; Oxford Nanopore Technologies, Oxford, UK., Liao W; New York Genome Center, New York, NY, USA., Augello MA; Department of Urology, Weill Cornell Medicine, New York, NY, USA.; Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA., Tyer C; Oxford Nanopore Technologies, New York, NY, USA., Rughani P; Oxford Nanopore Technologies, New York, NY, USA., Kudman S; Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, NY, USA., Tian H; Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA.; New York Genome Center, New York, NY, USA., Otis HG; New York Genome Center, New York, NY, USA.; Weill Cornell/Rockefeller/Sloan Kettering Tri-Institutional MD-PhD Program, New York, NY, USA., Adney E; Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA.; New York Genome Center, New York, NY, USA., Wilkes D; Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, NY, USA., Mosquera JM; Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA.; Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, NY, USA., Barbieri CE; Department of Urology, Weill Cornell Medicine, New York, NY, USA.; Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA.; Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, NY, USA., Melnick A; Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, NY, USA.; Division of Hematology/Oncology, Weill Cornell Medicine, New York, NY, USA., Stoddart D; Oxford Nanopore Technologies, Oxford, UK., Turner DJ; Oxford Nanopore Technologies, New York, NY, USA.; Oxford Nanopore Technologies, San Francisco, CA, USA.; Oxford Nanopore Technologies, Oxford, UK., Juul S; Oxford Nanopore Technologies, New York, NY, USA.; Oxford Nanopore Technologies, San Francisco, CA, USA.; Oxford Nanopore Technologies, Oxford, UK., Harrington E; Oxford Nanopore Technologies, New York, NY, USA., Imieliński M; Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA. mski@mskilab.org.; New York Genome Center, New York, NY, USA. mski@mskilab.org.; Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA. mski@mskilab.org.; Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, NY, USA. mski@mskilab.org.; Institute for Computational Biomedicine, Weill Cornell Medicine, New York, NY, USA. mski@mskilab.org.
Jazyk: angličtina
Zdroj: Nature biotechnology [Nat Biotechnol] 2022 Oct; Vol. 40 (10), pp. 1488-1499. Date of Electronic Publication: 2022 May 30.
DOI: 10.1038/s41587-022-01289-z
Abstrakt: High-order three-dimensional (3D) interactions between more than two genomic loci are common in human chromatin, but their role in gene regulation is unclear. Previous high-order 3D chromatin assays either measure distant interactions across the genome or proximal interactions at selected targets. To address this gap, we developed Pore-C, which combines chromatin conformation capture with nanopore sequencing of concatemers to profile proximal high-order chromatin contacts at the genome scale. We also developed the statistical method Chromunity to identify sets of genomic loci with frequencies of high-order contacts significantly higher than background ('synergies'). Applying these methods to human cell lines, we found that synergies were enriched in enhancers and promoters in active chromatin and in highly transcribed and lineage-defining genes. In prostate cancer cells, these included binding sites of androgen-driven transcription factors and the promoters of androgen-regulated genes. Concatemers of high-order contacts in highly expressed genes were demethylated relative to pairwise contacts at the same loci. Synergies in breast cancer cells were associated with tyfonas, a class of complex DNA amplicons. These results rigorously link genome-wide high-order 3D interactions to lineage-defining transcriptional programs and establish Pore-C and Chromunity as scalable approaches to assess high-order genome structure.
(© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)
Databáze: MEDLINE
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