The impact of changes in chromatin architecture on cancer phenotypes and tumor progression

点击翻译按钮获取中文摘要

SUMMARY - OVERALL Emerging data indicate that sets of genes are organized into boundary delimited territories and sub-territories, within which there is a high level of coordination of epigenetic marks and transcriptional states. The larger domains have been defined as compartments A and B that are respectively comprised of active and inactive chromatin. These can be broken down into conserved TADs (topologically associated domains). The latter are composed of highly self-interacting regions, segregated by insulated boundaries. At an even higher resolution level, gene expression is conferred through looping of cell context specific gene enhancers to promoters within, and less frequently beyond TAD boundaries. The most conserved TAD structural contacts are mediated and regulated at least in part through the action of CTCF, a DNA binding TF and boundary factor, along with the cohesin complex, while cell-type specific enhancer-promoter interactions are facilitated by cohesin, the mediator complex and cell transcription factors. Notably, CTCF and the cohesin complex are often mutated in cancer and play critical roles in normal development and differentiation pathways. They may also directly interact with, or indirectly control transcription factors and histone modifying complexes linked to malignant transformation. Based on these notions, our P01 proposes the following overall hypothesis: Somatic mutations of CTCF or cohesin regulators disrupt the architectural organization of chromatin (affecting TAD, and sub-TAD boundaries and enhancer interactions) and through this mechanism establish oncogenic epigenetic and transcriptional programs. Conversely, we propose that recruitment of architectural protein complexes are also disrupted by somatic mutation or deregulation of specific transcription factors, histone modifying enzymes and enzymes controlling DNA methylation, which place these changes upstream of alterations in chromosome architecture as a cause of tumorigenesis. To test our model we aim to compare the impact of mutations in CTCF, the cohesin unloading factor PDS5B, and proteins that control enhancer function (the NOTCH1 oncogenic transcription factor, histone modifying enzymes such as Polycomb and CREBBP/EP300, as well as enzymes that alter DNA methylation status DNMT3A). Focusing on hematologic malignancies we will: (i) determine whether and how mutations of Ctcf and the cohesin regulatory protein, Pds5b disrupt normal development and induce malignant transformation; (ii) determine how alterations in 3D chromosomal architecture caused by mutation of Ctcf or the cohesin regulator, Pds5b induce tumorigenic epigenetic and transcriptional programming; (iii) Determine whether transcription factors and mutations of epigenetic modifiers drive malignant transformation through effects on 3D chromosomal architecture; and (iv) determine whether drugs targeting transcription factor activity and epigenetic modifiers can `correct; the deleterious effects of oncogenic chromosomal architecture.