Disrupting the Code: Epigenetic Dysregulation of Lymphocyte Function during Infectious Disease and Lymphoma Development

Abstract

Lymphocyte differentiation and identity are controlled by signals in the microenvironment that ultimately mediate gene expression in the nucleus. Although much focus has centered on the strategic and often unique roles transcription factors play within lymphocyte subsets, it is increasingly clear that another level of molecular regulation is crucial for regulating gene expression programs. In particular, epigenetic regulation is critical for appropriately regulated temporal and cell-type-specific gene expression during immune responses. As such, mutations in epigenetic modifiers are linked with lymphomagenesis. Furthermore, certain infections can remodel the epigenome in host cells, either through the microenvironment or by directly co-opting host epigenetic mechanisms, leading to inappropriate gene expression and/or ineffective cellular behavior. This review will focus on how histone modifications and DNA methylation, and the enzymes that regulate the epigenome, underpin lymphocyte differentiation and function in health and disease.

Epigenetic regulation of B cell fate and function during an immune response

“…A key rationale for investigating the regulation of gene expression in human B cell populations is to understand how cellular behavior becomes dysregulated in disease. In particular, there is a clear translational pathway involving epigenetic regulators that are known to be dysregulated in B cell‐derived lymphomas . As such, there are a number of small molecule inhibitors targeting epigenetic regulators that are currently in clinical trials.…”

“…While there is some data to suggest that the transcriptome, but not DNA methylome, of naive B cells may differ depending on location, it is not clear whether there is differential recruitment of epigenetic modifiers during B cell differentiation depending either on the tissue‐specific site of the B cell response, or depending on whether they are located within a tissue or recirculating in the blood. This is important to decipher for a number of reasons, including: (a) determining the molecular determinants vital for an effective response to different types of pathogens, and (b) determining the extrinsic signals that drive context‐specific epigenetic regulation . Thus, understanding environment‐driven epigenetic regulation of B cell responses—to different pathogens, within different tissues—will be an important next step for the field.…”

“…In recent years researchers have focused on EZH2, one of two histone methyltransferases that are responsible for H3K27 methylation. Expression of EZH2 is dysregulated in germinal center‐derived lymphomas, such as in diffuse large B cell lymphoma, and therefore it is a critical clinical target . EZH2 has been found to have a critical contribution to germinal center formation and antibody production.…”

Antibody-secreting cell destiny emerges during the initial stages of B-cell activation

“…In addition to cell division, ASC differentiation requires the coordinated regulation of hundreds of genes, ultimately demanding differentiating cells to extinguish the B-cell program and initiate the ASC program 11 , 12 . In vivo, transcriptional rewiring and epigenetic remodeling 13 occur within the framework of cell division 14 – 18 . For example, DNA hypomethylation events occur in ASC predominately at enhancers and this is accompanied by a change in chromatin accessibility and gene expression 14 , 16 .…”

Chromatin Architecture as an Essential Determinant of Dendritic Cell Function

“…The genome-wide histone modification profile helps determine cellular identity in part by instructing binding events at specific chromosomal loci; histone modifications can alter the accessibility of transcriptional machinery at underlying genes, or can serve as beacons to recruit chromatin remodelers to either detect, deposit, or remove these histone marks (71). Any irregularities in this system can thus threaten cellular identity, potentially initiating disease (72, 73). Further, several studies have argued these irregularities to be the result of an emerging player in chromatin dynamics: altered cellular metabolism (40).…”