Abstract
Upon aging, the hematopoietic system undergoes changes leading to immunosenescence, anemia and increased incidence of malignancies. It is now clear that these clinical conditions are correlated with molecular changes in hematopoietic stem cells (HSCs) – a rare population of cells which are responsible for hematopoietic homeostasis throughout life. In order to determine consistent transcriptional changes between young and aged HSCs, we leveraged different published transcriptome studies which investigated changes between young and aged HSCs, including our own recently published set. We uncovered a significant degree of heterogeneity across studies, but nevertheless were able to distill a robust and consistent list of genes which are deregulated upon aging, termed the Aging Signature. Next, we sought to investigate whether genes in this signature show age-associated epigenetic alterations, further testing the hypothesis of epigenetic drifting in HSC aging. To this end we employed a multi-layer analysis of different epigenetic factors including chromatin accessibility, various histone modifications and DNA methylation between young and aged HSCs. This analysis demonstrated that aged cells consistently display an increased number of active histone marks (H3K4me3 and H3K36me3) and fewer repressive marks (H3K27me3). In addition, chromatin in aged HSCs is more loosely packed, and these cells show increased hypomethylation in regulatory genes of aging signature genes. This study corroborates the notion that upon aging overall HSCs lose repression of epigenetic modifications, leading to increased transcriptional activation. Upon aging, the hematopoietic system undergoes changes leading to immunosenescence, anemia and increased incidence of malignancies. It is now clear that these clinical conditions are correlated with molecular changes in hematopoietic stem cells (HSCs) – a rare population of cells which are responsible for hematopoietic homeostasis throughout life. In order to determine consistent transcriptional changes between young and aged HSCs, we leveraged different published transcriptome studies which investigated changes between young and aged HSCs, including our own recently published set. We uncovered a significant degree of heterogeneity across studies, but nevertheless were able to distill a robust and consistent list of genes which are deregulated upon aging, termed the Aging Signature. Next, we sought to investigate whether genes in this signature show age-associated epigenetic alterations, further testing the hypothesis of epigenetic drifting in HSC aging. To this end we employed a multi-layer analysis of different epigenetic factors including chromatin accessibility, various histone modifications and DNA methylation between young and aged HSCs. This analysis demonstrated that aged cells consistently display an increased number of active histone marks (H3K4me3 and H3K36me3) and fewer repressive marks (H3K27me3). In addition, chromatin in aged HSCs is more loosely packed, and these cells show increased hypomethylation in regulatory genes of aging signature genes. This study corroborates the notion that upon aging overall HSCs lose repression of epigenetic modifications, leading to increased transcriptional activation.
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