Biochemical link between epigenetic marks and chromatin remodelling
In plants, as in mammals, mutations in SNF2-like DNA helicases/ATPases were shown to affect not only chromatin structure but also global methylation patterns, suggesting a potential functional link between chromatin structure and epigenetic marks. The SNF2-like ATPase containing nucleosome remodelling and deacetylase corepressor complex (NuRD) is involved in gene transcriptional repression and chromatin remodelling. As mentioned above PML-RAR represses target genes through recruitment of DNMTs and Polycomb complex.
We have recently investigated a direct role of the NuRD complex in aberrant gene repression and transmission of epigenetic repressive marks in acute promyelocytic leukemia (APL). Our results indicate that PML-RAR binds and recruits NuRD to target genes, including to the tumor-suppressor gene RARß2. In turn, the NuRD complex facilities Polycomb binding and histone methylation at lysine 27. Retinoic acid treatment, which is often used for patients at the early phase of the disease, reduced the promoter occupancy of the NuRD complex. Knock-down of the NuRD complex in leukemic cells not only prevented histone deacetylation and chromatin compaction, but also impaired DNA and histone methylation as well as stable silencing, thus favouring cellular differentiation. These results unveil an important role for NuRD in the establishment of altered epigenetic marks in APL, demonstrating an essential link between chromatin structure and epigenetics in leukemogenesis.
Selected publications from our group on this research line:
- Villa R, Pasini D, Gutierrez A, Viré E, Nomdedeu JF, Jenuwein T, Pelicci PG, Minucci S, Fuks F, Helin K, and Di Croce L (2007) Role of the Polycomb repressive complex 2 in leukemia. Cancer Cell, 11, 513-525.
- Lee MG., Villa R., Trojer P., Norman J., Yan KP., Reinberg D., Di Croce L., Shiekhattar R. (2007) Demethylation of H3K27 regulates Polycomb recruitment and H2A ubiquitination. Science, 318, 447-450.
- Villa R., De Santis F., Raker V., Corsaro M., Gutierrez A., Buschbeck M., Morey L., Varas F., Bossi D., Minucci S., Pelicci PG. and Di Croce L. (2006) The methyl-CpG binding protein MBD1 is required for PML-RARα function. PNAS 103, 1400-1405.
- Di Croce, L., Raker V.A., Corsaro M., Fazi, F., Fanelli M., Fuks, F., Lo Coco, F., Kouzarides, T., Nervi, C., Minucci, S. and Pelicci, P.G. (2002) Methyltransferase recruitment and DNA hypermethylation of target promoters by an oncogenic transcription factor. Science 295, 1079-1082.