Abstract
The genomic loci associated with B cell differentiation that are subject to transcriptional and epigenetic regulation in vivo are not well defined, leaving a gap in our understanding of the development of humoral immune responses. Here, using an in vivo T cell independent B cell differentiation model, we define a cellular division-dependent cis-regulatory element road map using ATAC-seq. Chromatin accessibility changes correlate with gene expression and reveal the reprogramming of transcriptional networks and the genes they regulate at specific cell divisions. A subset of genes in naive B cells display accessible promoters in the absence of transcription and are marked by H3K27me3, an EZH2 catalyzed repressive modification. Such genes encode regulators of cell division and metabolism and include the essential plasma cell transcription factor Blimp-1. Chemical inhibition of EZH2 results in enhanced plasma cell formation, increased expression of the above gene set, and premature expression of Blimp-1 ex vivo. These data provide insights into cell-division coupled epigenetic and transcriptional processes that program plasma cells.
Highlights
The genomic loci associated with B cell differentiation that are subject to transcriptional and epigenetic regulation in vivo are not well defined, leaving a gap in our understanding of the development of humoral immune responses
An in vivo model system was developed that allowed the analysis of molecular and epigenetic events to be ascertained with respect to the number of cellular divisions that occur during B cell to plasma cell differentiation[2]
Acquisition of the surface molecule CD138 in tandem with decreased levels of B220 can be used as a marker for plasmablast and plasma cell formation[18]
Summary
The genomic loci associated with B cell differentiation that are subject to transcriptional and epigenetic regulation in vivo are not well defined, leaving a gap in our understanding of the development of humoral immune responses. Plasma cells possess distinct DNA methylation landscapes from their naive counterparts[6, 7], and in vivo models that integrate cellular division with epigenetic and transcriptional changes demonstrate a linkage between changes in DNA methylation and cellular division[2] These data revealed that few CpG loci gained DNA methylation, suggesting that other epigenetic processes facilitate gene repression during plasma cell formation[2]. BCL614 and Blimp-115 differentially recruit EZH2 to distinct regions of DNA to repress genes that dictate plasma cell and B cell fates, respectively, and demonstrate that sequence specific DNA-binding proteins can recruit epigenetic enzymes to distinct loci Such studies provide a potential mechanism for how changes in transcription factor networks facilitate remodeling of the epigenome during differentiation. These data provide a role for EZH2 dependent control of B cell fate that is orchestrated and regulated in a division-dependent manner
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