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Ig Enhancers Increase RNA Polymerase II Stalling at Somatic Hypermutation Target Sequences

A. Tarsalainen, Y. Maman, FL. Meng, MK. Kyläniemi, A. Soikkeli, P. Budzyńska, JJ. McDonald, F. Šenigl, FW. Alt, DG. Schatz, J. Alinikula

. 2022 ; 208 (1) : 143-154. [pub] 20211203

Language English Country United States

Document type Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't

Persistent link   https://www.medvik.cz/link/bmc22011513

Grant support
R01 AI127642 NIAID NIH HHS - United States
T32 AI007019 NIAID NIH HHS - United States
UL1 TR001863 NCATS NIH HHS - United States

Somatic hypermutation (SHM) drives the genetic diversity of Ig genes in activated B cells and supports the generation of Abs with increased affinity for Ag. SHM is targeted to Ig genes by their enhancers (diversification activators [DIVACs]), but how the enhancers mediate this activity is unknown. We show using chicken DT40 B cells that highly active DIVACs increase the phosphorylation of RNA polymerase II (Pol II) and Pol II occupancy in the mutating gene with little or no accompanying increase in elongation-competent Pol II or production of full-length transcripts, indicating accumulation of stalled Pol II. DIVAC has similar effect also in human Ramos Burkitt lymphoma cells. The DIVAC-induced stalling is weakly associated with an increase in the detection of ssDNA bubbles in the mutating target gene. We did not find evidence for antisense transcription, or that DIVAC functions by altering levels of H3K27ac or the histone variant H3.3 in the mutating gene. These findings argue for a connection between Pol II stalling and cis-acting targeting elements in the context of SHM and thus define a mechanistic basis for locus-specific targeting of SHM in the genome. Our results suggest that DIVAC elements render the target gene a suitable platform for AID-mediated mutation without a requirement for increasing transcriptional output.

References provided by Crossref.org

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