Transcription Elongation Can Affect Genome 3D Structure

Sven Heinz; Lorane Texari; Michael G B Hayes; Matthew Urbanowski; Max W Chang; Ninvita Givarkes; Alexander Rialdi; Kris M White; Randy A Albrecht; Lars Pache; Ivan Marazzi; Adolfo García-Sastre; Megan L Shaw; Christopher Benner

doi:10.1016/j.cell.2018.07.047

Transcription Elongation Can Affect Genome 3D Structure

Cell. 2018 Sep 6;174(6):1522-1536.e22. doi: 10.1016/j.cell.2018.07.047. Epub 2018 Aug 23.

Authors

Affiliations

¹ Department of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0640, USA. Electronic address: [email protected].
² Department of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0640, USA.
³ Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029-6574, USA.
⁴ Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029-6574, USA; Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029-6574, USA.
⁵ Infectious and Inflammatory Disease Center, Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
⁶ Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029-6574, USA; Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029-6574, USA; Division of Infectious Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029-6574, USA.
⁷ Department of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0640, USA. Electronic address: [email protected].

Abstract

How transcription affects genome 3D organization is not well understood. We found that during influenza A (IAV) infection, rampant transcription rapidly reorganizes host cell chromatin interactions. These changes occur at the ends of highly transcribed genes, where global inhibition of transcription termination by IAV NS1 protein causes readthrough transcription for hundreds of kilobases. In these readthrough regions, elongating RNA polymerase II disrupts chromatin interactions by inducing cohesin displacement from CTCF sites, leading to locus decompaction. Readthrough transcription into heterochromatin regions switches them from the inert (B) to the permissive (A) chromatin compartment and enables transcription factor binding. Data from non-viral transcription stimuli show that transcription similarly affects cohesin-mediated chromatin contacts within gene bodies. Conversely, inhibition of transcription elongation allows cohesin to accumulate at previously transcribed intragenic CTCF sites and to mediate chromatin looping and compaction. Our data indicate that transcription elongation by RNA polymerase II remodels genome 3D architecture.

Keywords: CTCF; NS1; chromatin compaction; cohesin; genome 3D structure; influenza A virus; readthrough transcription; transcription; transcription elongation; transcription termination.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Binding Sites
CCCTC-Binding Factor / chemistry
CCCTC-Binding Factor / metabolism
Carrier Proteins / antagonists & inhibitors
Carrier Proteins / genetics
Carrier Proteins / metabolism
Cell Cycle Proteins / metabolism
Cell Line
Chromatin / chemistry
Chromatin / metabolism*
Chromosomal Proteins, Non-Histone / metabolism
Cohesins
Flavonoids / pharmacology
Genome, Human*
Humans
Influenza A Virus, H5N1 Subtype / metabolism*
Interferon-beta / pharmacology
Macrophages / cytology
Macrophages / metabolism
Macrophages / virology
Nuclear Proteins / antagonists & inhibitors
Nuclear Proteins / genetics
Nuclear Proteins / metabolism
Piperidines / pharmacology
Protein Binding
Proto-Oncogene Proteins / antagonists & inhibitors
Proto-Oncogene Proteins / genetics
Proto-Oncogene Proteins / metabolism
RNA Interference
RNA Polymerase II / genetics
RNA Polymerase II / metabolism
RNA, Small Interfering / metabolism
Transcription, Genetic / drug effects
Viral Nonstructural Proteins / genetics
Viral Nonstructural Proteins / metabolism

Substances

CCCTC-Binding Factor
Carrier Proteins
Cell Cycle Proteins
Chromatin
Chromosomal Proteins, Non-Histone
Flavonoids
INS1 protein, influenza virus
Nuclear Proteins
Piperidines
Proto-Oncogene Proteins
RNA, Small Interfering
Viral Nonstructural Proteins
WAPL protein, human
alvocidib
Interferon-beta
RNA Polymerase II

Grants and funding

U19 AI106754/AI/NIAID NIH HHS/United States