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

Abstract

In this study we have interrogated the DNA methylome of myelofibrosis patients using high-density DNA methylation arrays. We detected 35,215 differentially methylated CpGs 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, the majorities of differentially methylated CpGs were located outside gene promoter regions and showed a significant association with enhancer regions. This enhancer aberrant hypermethylation showed a negative correlation with the expression of 27 genes in the myelofibrosis cohort. Of these, we focused on 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 the enhancer hypermethylation of ZFP36L1. Furthermore, in vitro rescue of ZFP36L1 expression had an impact in cell proliferation and induced apoptosis in SET-2 cell line indicating a possible role of ZFP36L1 as a tumor suppressor gene in myelofibrosis. We describe the DNA methylation profile of myelofibrosis, identifying extensive changes in enhancer elements and revealing ZFP36L1 as a novel candidate tumor suppressor gene.