Bach2 Promotes B Cell Receptor–Induced Proliferation of B Lymphocytes and Represses Cyclin-Dependent Kinase Inhibitors

Abstract

BTB and CNC homology 2 (Bach2) is a transcriptional repressor that is required for the formation of the germinal center (GC) and reactions, including class switch recombination and somatic hypermutation of Ig genes in B cells, within the GC. Although BCR-induced proliferation is essential for GC reactions, the function of Bach2 in regulating B cell proliferation has not been elucidated. In this study, we demonstrate that Bach2 is required to sustain high levels of B cell proliferation in response to BCR signaling. Following BCR engagement in vitro, B cells from <i>Bach2</i>-deficient (<i>Bach2</i>^-/-) mice showed lower incorporation of BrdU and reduced cell cycle progression compared with wild-type cells. <i>Bach2</i>^-/- B cells also underwent increased apoptosis, as evidenced by an elevated frequency of sub-G₁ cells and early apoptotic cells. Transcriptome analysis of BCR-engaged B cells from <i>Bach2</i>^-/- mice revealed reduced expression of the antiapoptotic gene <i>Bcl2l1</i> encoding Bcl-x_L and elevated expression of cyclin-dependent kinase inhibitor (CKI) family genes, including <i>Cdkn1a</i>, <i>Cdkn2a</i>, and <i>Cdkn2b</i> Reconstitution of Bcl-x_L expression partially rescued the proliferation defect of <i>Bach2</i>^-/- B cells. Chromatin immunoprecipitation experiments showed that Bach2 bound to the CKI family genes, indicating that these genes are direct repression targets of Bach2. These findings identify Bach2 as a requisite factor for sustaining high levels of BCR-induced proliferation, survival, and cell cycle progression, and it promotes expression of Bcl-x_L and repression of CKI genes. BCR-induced proliferation defects may contribute to the impaired GC formation observed in <i>Bach2</i>^-/- mice.