Sangamo BioSciences, Inc., Point Richmond Tech Center, 501 Canal Boulevard, Suite A100, Richmond, California 94804, USA
Address for correspondence: Dr. Fyodor D. Urnov, Sangamo BioSciences, Inc., Point Richmond Tech Center, 501 Canal Boulevard, Suite A100, Richmond, CA 94804. Voice: 510-970-6000 ext. 255; fax: 510-236-8951.
furnov{at}sangamo.com
Ann. N.Y. Acad. Sci. 983: 5-21 (2003).
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.
