Raquel
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- DNA methylation of enhancer elements in myeloid neoplasms: think outside the promoters?(MDPI AG, 2019) Martinez-Calle, N. (Nicolas); Raquel; Prosper-Cardoso, F. (Felipe); Aguirre-Ena, X. (Xabier)Gene regulation through DNA methylation is a well described phenomenon that has a prominent role in physiological and pathological cell-states. This epigenetic modification is usually grouped in regions denominated CpG islands, which frequently co-localize with gene promoters, silencing the transcription of those genes. Recent genome-wide DNA methylation studies have challenged this paradigm, demonstrating that DNA methylation of regulatory regions outside promoters is able to influence cell-type specific gene expression programs under physiologic or pathologic conditions. Coupling genome-wide DNA methylation assays with histone mark annotation has allowed for the identification of specific epigenomic changes that affect enhancer regulatory regions, revealing an additional layer of complexity to the epigenetic regulation of gene expression. In this review, we summarize the novel evidence for the molecular and biological regulation of DNA methylation in enhancer regions and the dynamism of these changes contributing to the fine-tuning of gene expression. We also analyze the contribution of enhancer DNA methylation on the expression of relevant genes in acute myeloid leukemia and chronic myeloproliferative neoplasms. The characterization of the aberrant enhancer DNA methylation provides not only a novel pathogenic mechanism for different tumors but also highlights novel potential therapeutic targets for myeloid derived neoplasms.
- New Epigenetic Targets in Multiple Myeloma(2019-02-06) Raquel; Prosper-Cardoso, F. (Felipe); Prosper, F. (Felipe); Aguirre-Ena, X. (Xabier)
- The proliferative history shapes the DNA methylome of B-cell tumors and predicts clinical outcome(2020) López-Guillermo, A. (Armando); Jares, P. (Pedro); Nadeu, F. (Ferran); Beekman, R. (Renée); Royo, R. (Romina); Zenz, T. (Thorsten); Delgado, J. (Julio); Seung-Tae, L. (Lee); Kulis, M. (Marta); Bea, S. (Silvia); Baumann, T. (Tycho); Castellano, G. (Giancarlo); Marincevic-Zuniga, Y. (Yanara); Wiemels, J. (Joseph); Raquel; Puente, X.S. (Xosé S.); Campo, E. (Elías); Nordlund, J. (Jessica); Lonnerholm, G. (Gudmar); Duran-Ferrer, M. (Martí); Queirós, A. (Ana); Rivas-Delgado, A. (Alfredo); Puiggros, M. (Montserrat); Prosper-Cardoso, F. (Felipe); Giné, E. (Eva); Clot, G. (Guillem); Aguirre-Ena, X. (Xabier); Oakes, C.C. (Christopher C.); López-Otín, C. (Carlos); Lu, J. (Junyan); Martín, S. (Silvia); Martin-Subero, J.I. (Jose Ignacio)We report a systematic analysis of the DNA methylation variability in 1,595 samples of normal cell subpopulations and 14 tumor subtypes spanning the entire human B-cell lineage. Differential methylation among tumor entities relates to differences in cellular origin and to de novo epigenetic alterations, which allowed us to build an accurate machine learning-based diagnostic algorithm. We identify extensive individual-specific methylation variability in silenced chromatin associated with the proliferative history of normal and neoplastic B cells. Mitotic activity generally leaves both hyper- and hypomethylation imprints, but some B-cell neoplasms preferentially gain or lose DNA methylation. We construct a DNA-methylation-based mitotic clock, called epiCMIT, whose lapse magnitude represents a strong independent prognostic variable in B-cell tumors and is associated with particular driver genetic alterations. Our findings reveal DNA methylation as a holistic tracer of B-cell tumor developmental history, with implications in differential diagnosis and the prediction of clinical outcome. Martin-Subero and colleagues analyze DNA methylation patterns in B-cell tumors and their normal cells of origin, and develop epiCMIT, a methylation-based mitotic clock with prognostic relevance.