TET2 deficiency reprograms the germinal center B cell epigenome and silences genes linked to lymphomagenesis.

Document Type

Article

Publication Date

6-17-2020

Keywords

JGM, JMG, JAXCC

JAX Source

Sci Adv 2020 Jun 17; 6(25):eaay5872

Volume

6

Issue

25

First Page

5872

Last Page

5872

ISSN

2375-2548

PMID

32596441

DOI

https://doi.org/10.1126/sciadv.aay5872

Grant

Jackson Laboratory Director's Innovation Fund, Jackson Laboratory Cancer Center New Investigator Award,GM133562, CA034196

Abstract

The TET2 DNA hydroxymethyltransferase is frequently disrupted by somatic mutations in diffuse large B cell lymphomas (DLBCLs), a tumor that originates from germinal center (GC) B cells. Here, we show that TET2 deficiency leads to DNA hypermethylation of regulatory elements in GC B cells, associated with silencing of the respective genes. This hypermethylation affects the binding of transcription factors including those involved in exit from the GC reaction and involves pathways such as B cell receptor, antigen presentation, CD40, and others. Normal GC B cells manifest a typical hypomethylation signature, which is caused by AID, the enzyme that mediates somatic hypermutation. However, AID-induced demethylation is markedly impaired in TET2-deficient GC B cells, suggesting that AID epigenetic effects are partially dependent on TET2. Last, we find that TET2 mutant DLBCLs also manifest the aberrant TET2-deficient GC DNA methylation signature, suggesting that this epigenetic pattern is maintained during and contributes to lymphomagenesis.

Comments

We thank S. Sampson from The Jackson Laboratory for editing this manuscript. We thank members of Li Lab and Melnick Lab for discussion, and we thank the Jackson Laboratory Computer Sciences team and the Research Informatics Technology group, both for technical support.

Link to Full Text

Share

COinS