Widespread Epigenetic Reprogramming in Aging Human Hematopoietic Stem Cells

Abstract

At the root of the hematopoietic hierarchy reside the Janus-faced hematopoietic stem cells (HSC), capable of both self-renewal and differentiation. Aging impairs HSC function, leading to increased self-renewal, reduced homing ability and a myeloid differentiation bias. In addition, hematopoietic cells acquire somatic mutations as they age, frequently affecting epigenetic modifier genes. In this dissertation work, I provide a comprehensive characterization of epigenomic changes during normal human HSC aging and demonstrate that aged HSCs undergo widespread reduction in H3K27ac, H3K4me1 and H3K4me3, with little change in H3K27me3. Age-associated loss of enrichment of the activating histone marks H3K27ac and H3K4me3 was particularly prominent at active enhancers and bivalent promoters, respectively. Functional annotation of enhancers lost with age suggests that enhancer deregulation may contribute to HSC myeloid bias and the immune impairments observed in older individuals. Focal changes in DNA methylation were also observed with age, affecting WNT and cadherin associated pathways, and at regions that may predispose to leukemogenesis. DNA 5-hydroxymethylation displayed age-related gains, targeting GATA and KLF binding sites. Concurrent with these epigenetic changes were transcriptional downregulation and mis-splicing of epigenetic modifiers, spliceosome components, transcription factors, including many in the KLF family, and LMNA, which is mutated in Hutchinson-Gilford progeria syndrome. Together, these results establish that multiple levels of epigenetic deregulation with age converge on key hematopoietic regulatory genes and pathways contributing to aged HSC dysfunction.