title: Cooperative transcriptional repression by BCL6 and BACH2 in germinal center B-cell differentiation.
abstract: 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.
authors.affiliation: Division of Hematology and Oncology, Weill Cornell Medical College, New York, NY; and.
authors.forename: Chuanxin
authors.initials: C
authors.lastname: Huang
authors.forename: Huimin
authors.initials: H
authors.lastname: Geng
authors.forename: Isaac
authors.initials: I
authors.lastname: Boss
authors.forename: Ling
authors.initials: L
authors.lastname: Wang
authors.forename: Ari
authors.initials: A
authors.lastname: Melnick
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000502:physiology*; D050976:Basic-Leucine Zipper Transcription Factors / Q000378:metabolism*; D002454:Cell Differentiation / Q000235:genetics*; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism*; D015536:Down-Regulation / Q000235:genetics; D018858:Germinal Center / Q000502:physiology*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D051560:Proto-Oncogene Proteins c-bcl-6; D012756:Sheep; D014158:Transcription, Genetic
chemical_list: C102109:Bach2 protein, mouse; D050976:Basic-Leucine Zipper Transcription Factors; C490010:Bcl6 protein, mouse; D004268:DNA-Binding Proteins; D051560:Proto-Oncogene Proteins c-bcl-6