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

Androgens Chromatin / genetics Humans Nanopore Sequencing Nanopores Transcription Factors / genetics

Journal

Nature biotechnology

ISSN: 1546-1696

Titre abrégé: Nat Biotechnol

Pays: United States

ID NLM: 9604648

Informations de publication

Date de publication:
10 2022

Historique:

received: 12 04 2020

accepted: 16 03 2022

pubmed: 1 6 2022

medline: 12 10 2022

entrez: 31 5 2022

Statut: ppublish

Résumé

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.

Identifiants

DOI: 10.1038/s41587-022-01289-z PMID: 35637420

pubmed: 35637420

doi: 10.1038/s41587-022-01289-z

pii: 10.1038/s41587-022-01289-z

doi:

Substances chimiques

Androgens 0

Chromatin 0

Transcription Factors 0

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

Pagination

1488-1499

Informations de copyright

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