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Intrinsic HSC aging
platelet genes expression at the expense of lymphopoietic genes, confirming the well-known myeloid skewing fea- ture of aged HSC.18,79
The suggested mechanisms underlying such a genome- wide transcriptional change are related to the epigenomic regulation. Indeed, there is much evidence to support this hypothesis. For example, by reprogramming young and aged murine hematopoietic progenitors, the repopulation potential is indistinguishable between young and aged derived iPS into all hematopoietic lineages in chimera indi- viduals and in HSC transplantations.49,78 These data imply that reprogramming is resetting the epigenetic state of the HSC regardless of the age at which the cells are repro- grammed. Moreover, these data also suggest that epige- netic alterations that occur upon aging are reversible.80,81
The epigenomic landscape of HSC has been shown to change with respect to DNA methylation, histone modifi- cations and chromatin architecture (Figure 2).
DNA methylation changes from young to aged hematopoietic stem cells
Global hypomethylation occurs in most somatic cells and in primary cells during aging.19,81 In contrast, the major-
ity of DNA methylation signatures during HSC aging in mice are highly conserved.27,28,82 However, the overall methylation change of aged HSC compared with young HSC is different depending on the study. The studies per- formed using reduce-representation bisulfite sequencing (RRBS)27,28 showed a slight tendency to hypermethylation with aging. In contrast Taiwo et al. reported a slight but significant (5%) global loss of DNA methylation by Me- DIP-seq. Taiwo et al. argue that the difference could be explained by the difference in coverage of each technique. Bisulfite-sequencing provides generally 5-10% genome coverage, in contrast with 60% provided by MeDIP-seq.82
Interestingly, independently from the overall hypo- or hypermethylation detected, all studies so far report high similarities in the alterations at specific loci that gained or lost methylation. One of the clearest examples involves polycomb repressive complex (PRC2) target genes, which are hypermethylated in aged HSC.27,82 It has been demon- strated in a human cell line that PRC2 cannot bind to chro- matin if the DNA is hypermethylated.83 Moreover, some PRC2 complex subunits in aged and proliferative stressed HSC resulted in being down-regulated as measured by RT-qPCR27 and RNA sequencing.28 These observations
Figure 2. The nuclear compartment in hematopoietic stem cells (HSC) during aging. The nuclear compartment undergoes several changes through aging, ranging from changes in histone post-translational modifications and DNA methylation to alterations of epi-polarity and chromatin architecture. Although the DNA damage repair (DDR) machinery is functional when entering in cycle from quiescence, DNA mutation and hematopoietic clonality can be detected and increase in frequency over time. CASIN treatment of aged HSC restores epi-polarity of H4K16ac, a nuclear hallmark of young HSC. K16ac: H4K16ac; met: DNA methylated; green me3: H3K4me3; red me3: H3K27me3. DDR: DNA damage repair.
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