Computational analysis of enhancer deregulation in Multiple Myeloma

Gene regulation is a complex process, which dictates how the body reacts to different situations through gene expression. Enhancers are sequences of a few hundred base pairs, involved in the regulation of transcription. This work focuses on enhancer activity changes during the cancer multiple myeloma, an incurable malignancy of the plasma cells: B-cells, which are long-lived, produce immunoglobin and provide protection against antigens that activated them. In this thesis, data from different assays is combined for multiple myeloma and plasma cells samples to determine cancer-specific and subgroup-specific enhancers and these are correlated with target genes based on activity of both actors. I find hundreds of enhancers linked to expression of nearby genes, with a large fraction of these being specific to MAF translocated tumors. Changes in de-novo open chromatin distant to the promoter of a gene are more predictive of gene expression than opening of the promoter. Also, combination of chromatin accessibility data and gene expression data is better at distinguishing cancer subtypes than either alone. Many of the regulated genes are known to be important in multiple myeloma, and this study provides a potential mechanism for their deregulation. In addition, I identify novel genes of interest. These enhancers show motif enrichment for transcription factors expressed in plasma cells as opposed to cancer specific factors. In particular, a large, MAF binding, open chromatin region is identified that correlates with the expression of the oncogene CCND2, and distinguishes mutually exclusive sets of samples expressing CCND2 or CCND1, going some way to explaining the known CCND dichotomy. This work lays the foundations of in vivo and de novo Myeloma vs. PC and MM subgroup specific enhancer – promoter interactions essential for the oncogenic state. Given that currently Myeloma is an incurable cancer, this should be of significant relevance for diagnosis, prognosis and treatment.