Poly(ADP-ribosyl)ation and epigenetics. Is CTCF PARt of the plot?

Despite the fact that the poly(ADP-ribose) (PAR) modification of proteins has been known for more than four decades, there is no unifying picture of the pathways governed by this process. While the function of poly(ADP-ribosyl)ation (PARlation) has shown to be traditionally associated with DNA repair and genotoxic stress, there is an emerging view that PARlation is also important in epigenetic regulation of chromatin structure and gene expression in the normal context. This view has been exemplified by the recent demonstration that PARlation is essential for the manifestation of the imprinted state of the Igf2 gene. In particular, the PARlation mark was shown to associate preferentially with the maternally inherited H19 ICR allele, this association depended on functional target sites of the chromatin insulator protein CTCF and, importantly, CTCF itself was found to be PARlated. Given that CTCF is currently the only known factor common for all vertebrate chromatin insulators, it is not surprising that the derepression of the maternal Igf2 allele by 3-aminobenzamide (an inhibitor of PAR polymerases) could be linked to a perturbed chromatin insulator function at the H19 ICR. This feature appears to extend to more than 150 chromatin insulators that were isolated due to their in vivo interaction with CTCF. In this review, we discuss in more depth these results and point out that the turnover of the PARlation mark at DNA-bound CTCF is indicative of a novel mode of rheostat control of expression domains possibly by regulating the stability of higher order chromatin conformations.