ARTÍCULO

Epigenomic profiling of myelofibrosis reveals widespread DNA methylation changes in enhancer elements and ZFP36L1 as a potential tumor suppressor gene that is epigenetically regulated

Autores: Martínez Calle, Nicolás; Pascual, M.; Ordóñez Ciriza, Raquel; San José Enériz, Edurne; Kulis, M.; Miranda, E.; Guruceaga Martínez, Elisabet; Segura Ruiz, Victoriano; Larráyoz Ilundáin, María José; Bellosillo, B.; Calasanz Abinzano, María José; Besses, C.; Rifón Roca, José Juan; Martin-Subero, J. I.; Agirre, X.; Prósper Cardoso, Felipe Luis (Autor de correspondencia)
Título de la revista: HAEMATOLOGICA
ISSN: 0390-6078
Volumen: 104
Número: 8
Páginas: 1572 - 1579
Fecha de publicación: 2019
Lugar: WOS
Resumen:
In this study we interrogated the DNA methylome of myelofibrosis patients using high-density DNA methylation arrays. We detected 35,215 differentially methylated CpG, corresponding to 10,253 genes, between myelofibrosis patients and healthy controls. These changes were present both in primary and secondary myelofibrosis, which showed no differences between them. Remarkably, most differentially methylated CpG were located outside gene promoter regions and showed significant association with enhancer regions. This aberrant enhancer hypermethylation was negatively correlated with the expression of 27 genes in the myelofibrosis cohort. Of these, we focused on the ZFP36L1 gene and validated its decreased expression and enhancer DNA hypermethylation in an independent cohort of patients and myeloid cell-lines. In vitro reporter assay and 5'-azacitidine treatment confirmed the functional relevance of hypermethylation of ZFP36L1 enhancer. Furthermore, in vitro rescue of ZFP36L1 expression had an impact on cell proliferation and induced apoptosis in SET-2 cell line indicating a possible role of ZFP36L1 as a tumor suppressor gene in myelofibrosis. Collectively, we describe the DNA methylation profile of myelofibrosis, identifying extensive changes in enhancer elements and revealing ZFP36L1 as a novel candidate tumor suppressor gene.