Chromatin and cancer: Causes and consequences

In this review, we discuss recent evidence implicating chromatin structure in the etiology of cancer. In particular, we present evidence indicating that inappropriate regulation of chromatin structure inhibits normal cell differentiation pathways and stimulates uncontrolled cell proliferation, with the outcome being oncogenesis. Such inappropriate chromatin structures arise as a consequence of (i) chromosomal rearrangements that fuse gene-specific activators with global co-regulators, drastically altering activator function; (ii) hypermethylation of tumor suppressor gene promoters, resulting in their inactivation; or (iii) mistargeted nuclear compartmentalization of growth-control genes and their regulators, resulting in the up- or down-regulation of such genes. How does chromatin silence genes? Recent results from model in vivo systems argues that chromatin can repress transcription ar two levels: (i) by sterically interfering with the binding of transcription factors to the promoter, thereby blocking initiation; and (ii) at a step subsequent to the binding of activators and recruitment of the preinitiation complex.