Donor age and C1orf132/MIR29B2C determine age-related methylation signature of blood after allogeneic hematopoietic stem cell transplantation

Abstract

BackgroundOur recent study demonstrated that DNA methylation status in a set of CpGs located in ELOVL2, C1orf132, TRIM59, KLF14, and FHL2 can accurately predict calendar age in blood. In the present work, we used these markers to evaluate the effect of allogeneic hematopoietic stem cell transplantation (HSCT) on the age-related methylation signature of human blood.MethodsDNA methylation in 32 CpGs was investigated in 16 donor-recipient pairs using pyrosequencing. DNA was isolated from the whole blood collected from recipients 27–360 days (mean 126) after HSCT and from the donors shortly before the HSCT.ResultsIt was found that in the recipients, the predicted age did not correlate with their calendar age but was correlated with the calendar age (r = 0.94, p = 4 × 10−8) and predicted age (r = 0.97, p = 5 × 10−10) of a respective donor. Despite this strong correlation, the predicted age of a recipient was consistently lower than the predicted age of a donor by 3.7 years (p = 7.8 × 10−4). This shift was caused by hypermethylation of the C1orf132 CpGs, for C1orf132 CpG_1. Intriguingly, the recipient-donor methylation difference correlated with calendar age of the donor (r = 0.76, p = 6 × 10−4). This finding could not trivially be explained by shifts of the major cellular factions of blood.ConclusionsWe confirm the single previous report that after HSCT, the age of the donor is the major determinant of age-specific methylation signature in recipient’s blood. A novel finding is the unique methylation dynamics of C1orf132 which encodes MIR29B2C implicated in the self-renewing of hematopoietic stem cells. This observation suggests that C1orf132 could influence graft function after HSCT.Electronic supplementary materialThe online version of this article (doi:10.1186/s13148-016-0257-7) contains supplementary material, which is available to authorized users.

Epigenetic age is a cell‐intrinsic property in transplanted human hematopoietic cells

“…Our observation is consistent with previous studies examining other types of age‐dependent DNAm levels in hematopoietic cells (Spolnicka et al, ; Weidner et al, ). In these previous studies, three (Weidner et al, ) or five (Spolnicka et al, ) CpG sites were analyzed after 4 months or 1 year after HSCT.…”

“…Experiments involving heterochronic parabiosis or the transfer of factors from human cord blood to old mice have demonstrated that factors present in the younger blood might rejuvenate older tissues (Castellano et al, ; Conboy, Conboy, & Rando, ; Eggel & Wyss‐Coray, ). On the other hand, recently published work suggests that the DNAm age of transplanted blood cells is maintained at the donor's age, at least under short‐term observations (Spolnicka et al, ; Stölzel et al, ; Weidner et al, ). However, it is not yet known if the DNAm age of the donor cells is affected by the recipient's age after prolonged exposure to the recipient's signaling environment.…”

“…Several publications describe DNA methylation (DNAm)‐based biomarkers of aging which can be used to estimate the age of a tissue (Hannum et al, ; Horvath, ; Spolnicka et al, ; Weidner & Wagner, ). For example, the multitissue age estimator utilizes the weighted average of 353 CpG sites to arrive at an age estimate that is referred to as DNAm age (Horvath, ).…”

“…Second, HSC donors were mostly younger than the recipients as opposed to the other way around. Third, Spolnicka et al () and Weidner et al () used blood cell‐specific DNAm age estimators, but not the multitissue DNAm age estimator. Fourth, children or adolescents were not included in any of these studies.…”

“…Fourth, children or adolescents were not included in any of these studies. Finally, these studies had a short follow‐up time, with a mean of 126 days, 1 year, and up to 8.8 years (Spolnicka et al, ; Stölzel et al, ; Weidner et al, ). The study by Stolzel et al involved recipients who were followed up for more than 12 months; however, the age difference between donor and recipient was not reported.…”