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

0555983 - ÚMG 2023 RIV US eng J - Článek v odborném periodiku
Tarsalainen, A. - Maman, Y. - Meng, F. - Kylaniemi, M. - Soikkeli, A. - Budzynska, P. - McDonald, J. - Šenigl, Filip - Alt, F. - Schatz, D. G. - Alinikula, J.
Ig Enhancers Increase RNA Polymerase II Stalling at Somatic Hypermutation Target Sequences.
Journal of Immunology. Roč. 208, č. 1 (2022), s. 143-154. ISSN 0022-1767. E-ISSN 1550-6606
Grant CEP: GA ČR GA15-24776S
Institucionální podpora: RVO:68378050
Klíčová slova: induced cytidine deaminase * class switch recombination * single-stranded-dna * b-cell genome * super-enhancers * deficiency causes * terminal domain * histone h3.3 * aid * transcription
Obor OECD: Immunology
Impakt faktor: 4.4, rok: 2022
Způsob publikování: Open access
https://journals.aai.org/jimmunol/article/208/1/143/234155/Ig-Enhancers-Increase-RNA-Polymerase-II-Stalling

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.
Trvalý link: http://hdl.handle.net/11104/0330835