Multiplex chromatin interactions with single-molecule precision.

Authors

Meizhen Zheng, The Jackson LaboratoryFollow
Simon Zhongyuan Tian, The Jackson LaboratoryFollow
Daniel Capurso, The Jackson LaboratoryFollow
Minji Kim, The Jackson LaboratoryFollow
Rahul Maurya, The Jackson LaboratoryFollow
Byoungkoo Lee, The Jackson LaboratoryFollow
Emaly Piecuch, The Jackson LaboratoryFollow
Liang Gong, The Jackson LaboratoryFollow
Jacqueline Jufen Zhu, The Jackson LaboratoryFollow
Zhihui Li
Chee-Hong Wong, The Jackson LaboratoryFollow
Chew Yee Ngan, The Jackson LaboratoryFollow
Ping Wang, The Jackson LaboratoryFollow
Xiaoan Ruan, The Jackson LaboratoryFollow
Chia-Lin Wei, The Jackson LaboratoryFollow
Yijun Ruan, The Jackson LaboratoryFollow

Document Type

Article

Publication Date

2-28-2019

Keywords

JGM

JAX Source

Nature 2019 Feb 28; 566(7745):558-562

Volume

566

Issue

7745

First Page

558

Last Page

562

ISSN

1476-4687

PMID

30778195

DOI

https://doi.org/10.1038/s41586-019-0949-1

Grant

The Jackson Laboratory Director's Innovation Fund, DK107967, Florine Roux Endowment

Abstract

The genomes of multicellular organisms are extensively folded into 3D chromosome territories within the nucleus¹. Advanced 3D genome-mapping methods that combine proximity ligation and high-throughput sequencing (such as chromosome conformation capture, Hi-C)², and chromatin immunoprecipitation techniques (such as chromatin interaction analysis by paired-end tag sequencing, ChIA-PET)³, have revealed topologically associating domains⁴ with frequent chromatin contacts, and have identified chromatin loops mediated by specific protein factors for insulation and regulation of transcription^5-7. However, these methods rely on pairwise proximity ligation and reflect population-level views, and thus cannot reveal the detailed nature of chromatin interactions. Although single-cell Hi-C⁸ potentially overcomes this issue, this method may be limited by the sparsity of data that is inherent to current single-cell assays. Recent advances in microfluidics have opened opportunities for droplet-based genomic analysis⁹ but this approach has not yet been adapted for chromatin interaction analysis. Here we describe a strategy for multiplex chromatin-interaction analysis via droplet-based and barcode-linked sequencing, which we name ChIA-Drop. We demonstrate the robustness of ChIA-Drop in capturing complex chromatin interactions with single-molecule precision, which has not been possible using methods based on population-level pairwise contacts. By applying ChIA-Drop to Drosophila cells, we show that chromatin topological structures predominantly consist of multiplex chromatin interactions with high heterogeneity; ChIA-Drop also reveals promoter-centred multivalent interactions, which provide topological insights into transcription.

Recommended Citation

Zheng M, Tian S, Capurso D, Kim M, Maurya R, Lee B, Piecuch E, Gong L, Zhu J, Li Z, Wong C, Ngan C, Wang P, Ruan X, Wei C, Ruan Y. Multiplex chromatin interactions with single-molecule precision. Nature 2019 Feb 28; 566(7745):558-562