Integrative transcriptome and chromatin landscape analysis reveals distinct epigenetic regulations in human memory B cells

Justin B Moroney,Hong Zan,Anusha Vasudev,Paolo Casali,Alexander Pertsemlidis

doi:10.1038/s41467-020-19242-6

Abstract

Memory B cells (MBCs) are long-lived and produce high-affinity, generally, class-switched antibodies. Here, we use a multiparameter approach involving CD27 to segregate naïve B cells (NBC), IgD+ unswitched (unsw)MBCs and IgG+ or IgA+ class-switched (sw)MBCs from humans of different age, sex and race. Conserved antibody variable gene expression indicates that MBCs emerge through unbiased selection from NBCs. Integrative analyses of mRNAs, miRNAs, lncRNAs, chromatin accessibility and cis-regulatory elements uncover a core mRNA-ncRNA transcriptional signature shared by IgG+ and IgA+ swMBCs and distinct from NBCs, while unswMBCs display a transitional transcriptome. Some swMBC transcriptional signature loci are accessible but not expressed in NBCs. Profiling miRNAs reveals downregulated MIR181, and concomitantly upregulated MIR181 target genes such as RASSF6, TOX, TRERF1, TRPV3 and RORα, in swMBCs. Finally, lncRNAs differentially expressed in swMBCs cluster proximal to the IgH chain locus on chromosome 14. Our findings thus provide new insights into MBC transcriptional programs and epigenetic regulation, opening new investigative avenues on these critical cell elements in human health and disease.

Highlights

Memory B cells (MBCs) are long-lived and produce high-affinity, generally, class-switched antibodies
Different miRNA profiles have been reported in different B cell subsets, including MBCs37, and long non-coding RNAs (lncRNAs) have been associated with different stages of B cell development[38], no comprehensive analysis of the protein-coding and non-coding transcriptome and chromatin accessibility has been reported in human MBCs
This allowed for the identification of four distinct subsets: CD27–IgD+ naïve B cells (NBC) (63.9 ± 14.3%), CD27+IgD+ unswMBCs (9.7 ± 8.3%), CD27+IgG+ swMBCs (6.5 ± 3.1%) and CD27+IgA+ swMBCs (4.9 ± 2.0%)

Summary

Introduction

Memory B cells (MBCs) are long-lived and produce high-affinity, generally, class-switched antibodies. As we and others have shown, coordinated regulation of gene networks is critical in human and mouse B cell differentiation and antibody responses[26,27,28,29,30,31,32,33] Such coordinated regulation is mediated by epigenetic modifications and factors, including DNA methylation, histone post-translational modifications, and non-coding RNAs (ncRNAs), such as microRNAs (miRNAs) and long non-coding RNAs (lncRNAs)[34,35]. These layers of epigenetic regulation synergize with TFs and chromatin accessibility to outline distinct gene expression programs, thereby dictating cell functions[26,36]. Different miRNA profiles have been reported in different B cell subsets, including MBCs37, and lncRNAs have been associated with different stages of B cell development[38], no comprehensive analysis of the protein-coding and non-coding transcriptome and chromatin accessibility has been reported in human MBCs

Methods

Results

Conclusion