Bookmarking promoters in mitotic chromatin: poly(ADP-ribose)polymerase-1 as an epigenetic mark.
Bottom Line: After mitosis, it is thought that bookmarking transcription factors remain at promoters, regulating which genes become active and which remain silent.Herein, we demonstrate that poly(ADP-ribose)polymerase-1 (PARP-1) is a genome-wide epigenetic memory mark in mitotic chromatin, and we further show that the presence of PARP-1 is absolutely crucial for reactivation of transcription after mitosis.Based on these findings, a novel molecular model of epigenetic memory transmission through the cell cycle is proposed.
Affiliation: Fox Chase Cancer Center, Philadelphia, PA, 19111 USA.Show MeSH
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Mentions: To address which specific genes are marked by PARP-1 during mitosis, we performed consensus sequence comparison for the mitotic and interphase sites of PARP-1 occupancy. This analysis revealed GGAAAGG consensus sequences in proximity to approximately 65% of all sites of PARP-1 localization in mitosis and interphase (Figure 4A and Supplementary Figure S6). This sequence is similar to the known binding sites of transcriptional factor NFATC2 (51). NFATC2 serves as a transcriptional factor controlling inducible expression of interleukin gene family (52,53). Recent research has shown that transcription factors from NFAT family act as regulators of oncogenic transformation (54,55). NFATC2 remains bound to chromatin during interphase, as does PARP-1 (Figure 4B). We determined NFATC2 occupancy at a randomly selected group of PARP-1-positive peaks. Indeed, three tested PARP-1-positive loci OR51B2, ZSCAN4 and RRAS2 demonstrated significant occupancy by NFATC2, while the PARP-1 negative locus TMCC2 showed no NFATC2 binding in either mitosis or interphase (Figure 4C–D). Genome-wide co-occurrence of PARP-1 and NFATC2 binding sites suggests that genes marked by PARP-1 may share a common mechanism of regulation by NFATC2. This hypothesis is supported by earlier reports that NFATC2 directly interacts with PARP-1 and PARP-1 mediated poly(ADP-ribosyl)ation (56,57).
Affiliation: Fox Chase Cancer Center, Philadelphia, PA, 19111 USA.