Chromatin as a tool for the study of genome function in cancer.
The transition to malignancy requires an extensive reconfiguration of the genome's expression program that does not result entirely from actual changes in primary DNA sequence-i.e., mutation. Epigenetic-meta-DNA-gene expression states result from an assembly over a given locus of a poorly understood nucleoprotein entity that includes histones and other architectural components of chromatin, nonhistone DNA-bound regulators, and additional chromatin-bound polypeptides. This structure is rapidly reestablished in the wake of the DNA replication fork, thus ensuring its persistence in rapidly proliferating cells and thereby yielding an exceptionally stable mode of gene expression. Chromatin is the perfect vehicle for enabling such genome control. During S phase both covalently modified histones and histone-associated regulatory proteins distribute to the newly synthesized daughter chromatids in a form of "molecular dowry" inherited from the G(1) state of the genome, and impose a specific mode of function on the underlying DNA. An extensively studied example of chromatin-based epigenetic inheritance connects DNA methylation to the targeting of chromatin remodeling and modification. In a broad sense, however, genome reprogramming in cancer is associated with the remodeling of a multitude of regulatory DNA stretches-e.g., promoters, enhancers, locus control regions (LCRs), insulators, etc.-into a specific chromatin architecture. This architectural entity provides a general molecular signature of the cancer epigenome that complements and significantly expands its DNA methylation-based component.
Sangamo BioSciences, Inc., Point Richmond Tech Center, 501 Canal Boulevard, Suite A100, Richmond, California 94804, USA. furnov@sangamo.com
Fyodor D
FD
Urnov
D002843:Chromatin / Q000235:genetics*; D004273:DNA, Neoplasm / Q000235:genetics; D016678:Genome; D006801:Humans; D009369:Neoplasms / Q000235:genetics*; D014158:Transcription, Genetic
D002843:Chromatin; D004273:DNA, Neoplasm