Abstract
Epigenetic deregulation is considered a common hallmark of cancer. Nevertheless, recent publications have demonstrated its association with a large array of human diseases. Here, we explore the DNA methylation dynamics in blood samples during hematopoietic cell transplant and how they are affected by pathophysiological events during transplant evolution. We analyzed global DNA methylation in a cohort of 47 patients with allogenic transplant up to 12 months post-transplant. Recipients stably maintained the donor’s global methylation levels after transplant. Nonetheless, global methylation is affected by chimerism status. Methylation analysis of promoters revealed that methylation in more than 200 genes is altered 1 month post-transplant when compared with non-pathological methylation levels in the donor. This number decreased by 6 months post-transplant. Finally, we analyzed methylation in IFN-γ, FASL, IL-10, and PRF1 and found association with the severity of the acute graft-versus-host disease. Our results provide strong evidence that methylation changes in blood are linked to underlying physiological events and demonstrate that DNA methylation analysis is a viable strategy for the study of transplantation and for development of biomarkers.
Highlights
DNA methylation is an epigenetic regulatory mechanism essential for cellular differentiation processes and maintenance of cell type-specific gene expression patterns [1,2,3,4]
We analyzed DNA methylation of the LINE1 element which is an interspersed repetitive DNA element that comprises a substantial portion of the genome [25], and the pericentromeric tandem repeat NBL2 [26] in 47 patients after hematopoietic cell transplant by pyrosequencing (Table 1)
We evaluated the levels of methylation in the donors and in the recipients before and after the transplant and calculated a differential of methylation (DMet) that simultaneously compared the methylation values of all CpG sites analyzed in the amplicon between two samples (Figure 1A)
Summary
DNA methylation is an epigenetic regulatory mechanism essential for cellular differentiation processes and maintenance of cell type-specific gene expression patterns [1,2,3,4]. Each cell type possesses a stable and characteristic DNA methylation landscape that defines them. Environmental and physiopathological pressures can provoke DNA methylation changes [5,6,7]. Modifications in DNA methylation occur in response to environmental factors such as diet [7]. A large number of publications have revealed the fundamental link between epigenetic deregulation and human disease and DNA methylation is gaining increasing importance as a source of biomarkers and promising therapeutic targets [15]
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