GSE69558
Detection of Enhancer-Associated Rearrangements Reveals Mechanisms of Oncogene Dysregulation in B-cell Lymphoma [ChIP-Seq]
B-cell lymphomas frequently demonstrate inter-chromosomal translocations that lead to oncogene activation by heterologous distal regulatory elements.  We utilized a novel approach, termed 'Pinpointing of Enhancer-Associated Rearrangements by Chromatin Immunoprecipitation' or PEAR-ChIP, to simultaneously map enhancer activity and proximal rearrangements in lymphoma cell lines and patient biopsies. The method efficiently detects rearrangements within and adjacent to known cancer genes such as CCND1, BCL2, MYC, PDCD1LG2, NOTCH1, CIITA, and SGK1, as well as novel enhancer duplication events of likely oncogenic significance. We identify novel enhancer-like elements in the MYC locus that interact with the MYC promoter, are associated with germline polymorphisms that alter lymphoma risk, show lymphoma subtype-specific acetylation, and are silenced in lymphomas where MYC is activated by “enhancer hijacking” translocations. We also identify an array of BCL6-interacting enhancers that are subject to genomic alterations, are acetylated by the BCL6-activating transcription factor MEF2B, and target the MYC promoter in the context of a “pseudo-double-hit” t(3;8) genomic rearrangement linking the BCL6 and MYC loci. Our findings uncover diverse mechanisms by which genomic rearrangements can lead to aberrations in enhancer-mediated oncogene regulation. Overall design: Examination of histone modifications and transcription factors in lymphoma cell lines and primary patient samples