TitleCooperative transcriptional repression by BCL6 and BACH2 in germinal center B-cell differentiation.
Publication TypeJournal Article
Year of Publication2014
AuthorsHuang, ChuanXin, Geng Huimin, Boss Isaac, Wang Ling, and Melnick Ari
Date Published2014 Feb 13
KeywordsAnimals, B-Lymphocytes, Basic-Leucine Zipper Transcription Factors, Cell Differentiation, Cells, Cultured, DNA-Binding Proteins, Down-Regulation, Germinal Center, Humans, Mice, Mice, Transgenic, Proto-Oncogene Proteins c-bcl-6, Sheep, Transcription, Genetic

<p>The transcriptional repressors BCL6 and BACH2 are crucial regulators of germinal center (GC) B-cell fate, and are known to interact and repress transcription of PRDM1, a key driver of plasma cell differentiation. How these factors cooperate is not fully understood. Herein, we show that GC formation is only minimally impaired in Bcl6(+/-) or Bach2(+/-) mice, although double heterozygous Bcl6(+/-)Bach2(+/-) mice exhibit profound reduction in GC formation. Splenic B cells from Bcl6(+/-) Bach2(+/-) mice display accelerated plasmacytic differentiation and high expression of key plasma cell genes such as Prdm1, Xbp1, and CD138. Chromatin immunoprecipitation sequencing revealed that in B cells, BACH2 is mostly bound to genes together with its heterodimer partner MAFK. The BACH2-MAFK complex binds to sets of genes known to be involved in the GC response, 60% of which are also targets of BCL6. Approximately 30% of BACH2 peaks overlap with BCL6, including cis-regulatory sequences of the PRDM1 gene. BCL6 also modulates BACH2 protein stability and their protein levels are positively correlated in GC B cells. Therefore, BCL6 and BACH2 cooperate to orchestrate gene expression patterning in GC B cells through both transcriptional and biochemical mechanisms, which collectively determine the proper initiation and timing of terminal differentiation.</p>

Alternate JournalBlood
PubMed ID24277074
PubMed Central IDPMC3924924
Grant ListR01 CA104348 / CA / NCI NIH HHS / United States
NCI-R01 104348 / / PHS HHS / United States