Accumulation of the FACT complex, as well as histone H3.3, serves as a target marker for somatic hypermutation

Masatoshi Aida; Nesreen Hamad; Andre Stanlie; Nasim A Begum; Tasuku Honjo

doi:10.1073/pnas.1305859110

Accumulation of the FACT complex, as well as histone H3.3, serves as a target marker for somatic hypermutation

Proc Natl Acad Sci U S A. 2013 May 7;110(19):7784-9. doi: 10.1073/pnas.1305859110. Epub 2013 Apr 22.

Authors

Masatoshi Aida¹, Nesreen Hamad, Andre Stanlie, Nasim A Begum, Tasuku Honjo

Affiliation

¹ Department of Immunology and Genomic Medicine, Graduate School of Medicine, Kyoto University, Yoshida Sakyo-ku, Kyoto 606-8501, Japan.

Abstract

Somatic hypermutation (SHM) requires not only the expression of activation-induced cytidine deaminase, but also transcription in the target regions. However, how transcription guides activation-induced cytidine deaminase in targeting SHM to the Ig genes is not fully understood. Here, we found that the "facilitates chromatin transcription" (FACT) complex promotes SHM by RNAi screening of transcription elongation factors. Furthermore, FACT and histone H3.3, a hallmark of transcription-coupled histone turnover, are enriched at the V(D)J region, 5' flanking sequence of the Sμ switch region and the light chain Jκ 5 segment region in the Ig loci. The regions with the most abundant deposition of FACT and H3.3 were also the most efficient targets of SHM. These results demonstrate the importance of histone-exchanging dynamics at the chromatin of SHM targets, especially in Ig genes.

Keywords: AID; SSRP1.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Cell Line, Tumor
Chromatin / chemistry*
Chromatin / metabolism
Cinnamates / metabolism
Cytidine Deaminase / genetics
DNA Mutational Analysis
DNA-Binding Proteins / genetics
DNA-Binding Proteins / metabolism*
Genes, Reporter
Genetic Markers
Green Fluorescent Proteins / metabolism
High Mobility Group Proteins / genetics
High Mobility Group Proteins / metabolism*
Histones / genetics*
Humans
Hygromycin B / analogs & derivatives
Hygromycin B / metabolism
Immunoglobulin Class Switching
Immunoglobulins / genetics
RNA Interference
RNA, Small Interfering / metabolism
Sequence Analysis, DNA
Somatic Hypermutation, Immunoglobulin*
Transcription, Genetic
Transcriptional Elongation Factors / genetics
Transcriptional Elongation Factors / metabolism*

Substances

Chromatin
Cinnamates
DNA-Binding Proteins
Genetic Markers
High Mobility Group Proteins
Histones
Immunoglobulins
RNA, Small Interfering
SSRP1 protein, human
Transcriptional Elongation Factors
Green Fluorescent Proteins
Hygromycin B
hygromycin A
AICDA (activation-induced cytidine deaminase)
Cytidine Deaminase