Differential regulation of chromatin structure of the murine 3′ IgH enhancer and IgG2b germline promoter in response to lipopolysaccharide and CD40 signaling

Abstract

Class switch recombination (CSR) of murine immunoglobulin heavy chain (IgH) is controlled by germline transcription-coupled modification of the accessibility of the highly repetitive switch regions (S) located upstream of the constant region genes. Activation of the 3′ IgH enhancer (3′E) is believed to regulate CSR during B cell terminal differentiation, although the detailed molecular mechanism remains unclear. Here, we show that BAF57 and BRG1, two essential subunits of murine SWI/SNF complex, differentially associate with the DNase I hypersensitive region HS1/2 of 3′E and the IgG2b germline promoter in response to LPS activation or CD40 engagement. Both LPS and CD40 signaling cause SWI/SNF complex to dissociate from HS1/2 and associate with their responsive IgG2b germline promoter, suggesting the potential fluidity of chromatin structure and specific regulatory mode for the ATP-dependent chromatin remodeler during CSR. More interesting, increase in histone acetylation is either inverse or parallel with the action of SWI/SNF complex at HS1/2 enhancer or IgG2b germline promoter, respectively. Chromatin immunoprecipitation experiments show that alteration of histone H3 and H4 acetylation has overall similarities in response to LPS and CD40 signaling, with H3 hyperacetylated and H4 hypoacetylated at the HS1/2 enhancer and reversed modification patterns at the IgG2b germline promoter. Finally, the specificity of LPS and CD40 signaling in control of CSR could be partially coded by the specific acetylation marking of H3 and H4. Our results further strengthen the notion that chromatin remodeling plays a critical role in CSR.