4.6 Article

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

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JOURNAL OF IMMUNOLOGY
卷 208, 期 1, 页码 143-154

出版社

AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.2100923

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资金

  1. Israel Science Foundation [1920/20]
  2. Czech Science Foundation Grant [15-24776S]
  3. National Institutes of Health [AI 127642, T32 AI 007019]
  4. Sigrid Juselius Foundation
  5. Jane and Aatos Erkko Foundation
  6. Jenny and Antti Wihuri Foundation
  7. Ella and Georg Ehrnrooth Foundation
  8. Cancer Society of South-West Finland
  9. Emil Aaltonen Foundation
  10. Turku University Foundation
  11. Maud Kuistila Memorial Foundation
  12. K. Albin Johanssons Foundation

向作者/读者索取更多资源

Somatic hypermutation is driven by DIVACs, which increase phosphorylation and occupancy of RNA polymerase II, leading to accumulation of stalled Pol II and locus-specific targeting of SHM.
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.

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