Elemento, OlivierTeater, Matt2019-03-262019-03-272017https://hdl.handle.net/1813/64734A hallmark of diffuse large B cell lymphoma (DLBCL) pathogenesis is the perturbation of epigenetic mechanisms. Germinal center (GC) B cells, from which DLBCL originates, are characterized by a specialized phenotype enabling rapid proliferation, sustained replicative potential, and tolerance to DNA damage. This GC phenotype facilitates affinity maturation by supporting clonal expansion with concurrent mutations and rearrangements of the B cell receptor gene. We found that cytosine methylation patterns in GC B cells involve relative loss of methylation and acquisition of methylation heterogeneity. We found these effects to be largely mediated by AICDA, the enzyme responsible for somatic hypermutation of immunoglobulin loci. In DLBCL, expression of AICDA leads to increased epigenetic heterogeneity, a feature linked with poor clinical outcome. The GC phenotype is also mediated in part by histone modifications. We found that the histone methyltransferase EZH2 is required for GC formation and promotes the GC phenotype by silencing proliferation checkpoint and differentiation genes via repressive H3K27me3 modification of their promoters. Notably, we found that key regulatory loci implicated in GC exit are modified by EZH2 to establish GC-specific bivalent chromatin domains. We found that repression of these GC-specific bivalent domains requires cooperation of EZH2 with the BCL6 transcriptional repressor and a noncanonical PRC1 complex. Somatic mutations enhancing the activity of EZH2 or BCL6 can “lock in” certain oncogenic features of GC B cells, resulting in malignant transformation.en-USAttribution-NonCommercial-NoDerivatives 4.0 InternationalAICDAEpigeneticsEZH2Lymphomadissertation or thesis