RT Journal Article
SR Electronic
T1 TET2 deficiency reprograms the germinal center B cell epigenome and silences genes linked to lymphomagenesis
JF Science Advances
JO Sci Adv
FD American Association for the Advancement of Science
SP eaay5872
DO 10.1126/sciadv.aay5872
VO 6
IS 25
A1 Rosikiewicz, Wojciech
A1 Chen, Xiaowen
A1 Dominguez, Pilar M.
A1 Ghamlouch, Hussein
A1 Aoufouchi, Said
A1 Bernard, Olivier A.
A1 Melnick, Ari
A1 Li, Sheng
YR 2020
UL http://advances.sciencemag.org/content/6/25/eaay5872.abstract
AB 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.