Principles and methods of integrative chromatin analysis in primary tissues and tumors

Recent methodological advances have enabled the genome-wide interrogation of chromatin from primary tumor tissues. Integrative analysis of histone post-translational modifications, transcription factor (TF) binding and open chromatin sites in tumors across cancer stages can elucidate the aberrant epigenetic states accompanying tumor progression. Cancer-associated chromatin alterations can activate or inactivate enhancers at genes involved in cancer while still respecting cell-of-origin constrictions. Accordingly, enhancer analysis in cancer could have uses for biomarker discovery to further refine patient diagnosis and potentially sub-classify patients for tailored therapy. Methodologies used for chromatin analyses of primary tissues need to address issues distinct from cell line studies including the specific sources of variability coming from the heterogeneous cellular composition of tissues and from inter-individual (epi)genetic differences. This leads to requirements for careful histological analysis to select the specific samples and cells of interest. In analyzing tumors somatic changes should be taken into account to distinguish the genuine epigenetic changes across tumor specimens from any genetic alterations such as copy number variations (CNV). In this contribution we review a selection of current results from chromatin profiling, examine experimental methodologies and discuss specific analysis approaches. We also review specific considerations regarding tissue preparation for epigenetic analysis and conclude with our perspectives on emerging approaches that will impact studies of chromatin landscapes of clinical samples in the future.