Topologically Associated Domains Delineate Susceptibility to Somatic Hypermutation

Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved..

Somatic hypermutation (SHM) introduces point mutations into immunoglobulin (Ig) genes but also causes mutations in other parts of the genome. We have used lentiviral SHM reporter vectors to identify regions of the genome that are susceptible ("hot") and resistant ("cold") to SHM, revealing that SHM susceptibility and resistance are often properties of entire topologically associated domains (TADs). Comparison of hot and cold TADs reveals that while levels of transcription are equivalent, hot TADs are enriched for the cohesin loader NIPBL, super-enhancers, markers of paused/stalled RNA polymerase 2, and multiple important B cell transcription factors. We demonstrate that at least some hot TADs contain enhancers that possess SHM targeting activity and that insertion of a strong Ig SHM-targeting element into a cold TAD renders it hot. Our findings lead to a model for SHM susceptibility involving the cooperative action of cis-acting SHM targeting elements and the dynamic and architectural properties of TADs.

Medienart:

E-Artikel

Erscheinungsjahr:

2019

Erschienen:

2019

Enthalten in:

Zur Gesamtaufnahme - volume:29

Enthalten in:

Cell reports - 29(2019), 12 vom: 17. Dez., Seite 3902-3915.e8

Sprache:

Englisch

Beteiligte Personen:

Senigl, Filip [VerfasserIn]
Maman, Yaakov [VerfasserIn]
Dinesh, Ravi K [VerfasserIn]
Alinikula, Jukka [VerfasserIn]
Seth, Rashu B [VerfasserIn]
Pecnova, Lubomira [VerfasserIn]
Omer, Arina D [VerfasserIn]
Rao, Suhas S P [VerfasserIn]
Weisz, David [VerfasserIn]
Buerstedde, Jean-Marie [VerfasserIn]
Aiden, Erez Lieberman [VerfasserIn]
Casellas, Rafael [VerfasserIn]
Hejnar, Jiri [VerfasserIn]
Schatz, David G [VerfasserIn]

Links:

Volltext

Themen:

Activation induced deaminase
Chromatin loop extrusion
Chromatin structure
Cytidine Deaminase
EC 2.7.7.-
EC 3.5.4.5
Journal Article
RNA Polymerase II
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Somatic hypermutation
Topologically associated domain
Transcription factor

Anmerkungen:

Date Completed 14.09.2020

Date Revised 10.01.2021

published: Print

Citation Status MEDLINE

doi:

10.1016/j.celrep.2019.11.039

funding:

Förderinstitution / Projekttitel:

PPN (Katalog-ID):

NLM304526703