Mapping of histone modifications in aged hematopoietic stem cells (HSCs)
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE120232 | GEO | 2018/09/20
REPOSITORIES: GEO
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Project description:The decline of hematopoietic stem cell (HSC) function upon aging contributes to the senescent immune remodeling and to leukemia pathogenesis. Aged HSCs show changes in their epigenome, like alterations in the global and local DNA/histone methylation and histone acetylation landscape. Previously, we showed a correlation between high Cdc42 activity and the loss of intra-nuclear epigenetic polarity (epipolarity), as indicated by the specific location of histone H4 lysine 16 acetylation (H4K16ac). Here, we show that not all histone modifications display a polar localization and that loss of H4K16ac amount and epipolarity is specific to aged HSCs. Increased levels of H4K16ac are insufficient to restore polarity in aged HSCs and for the restoration of HSC function. Changes in H4K16ac upon aging and rejuvenation of HSCs are correlated to a shift of chromosome 11 architecture and nuclear volume and shape. Surprisingly, by taking advantage of knock-out mouse models we demonstrate that increased Cdc42 activity levels correlate with the repression of LaminA/C expression, which control chromosome 11 distribution, H4K16ac polarity and the nuclear volume and shape of aged HSCs. These chromatin and epigenetic architecture changes are targeted by altering the activity of the small RhoGTPase Cdc42, that regulates LaminA/C. Collectively, our data show that chromatin architecture changes in stem cells are reversible by changing levels of Cdc42 activity, revealing an unanticipated way to pharmacologically target LaminA/C expression and revert alterations of the epigenetic architecture in aged HSCs.
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Project description:Mapping of histone modifications in aged hematopoietic stem cells (HSCs)
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Project description:Leptin receptor (LEPR) identifies a subpopulation of hematopoietic stem cells (HSCs) with high repopulating potential. In this study, we demonstrated that LEPR-expressing HSCs while exhibiting significantly higher engrafting potential and self-renewing capacity in young mice showed early age-associated decline in these functions as compared to the LEPR- HSCs. LEPR+ HSCs have transcriptomic profiles significantly different from LEPR- HSCs in young mouse bone marrow, but middle-aged HSCs do not have distinct transcriptomic profiles based on LEPR status. The age-related phenotypes were associated with a proinflammatory transcriptomic profile at baseline in young LEPR+ HSCs, which was further exacerbated by age. In contrast, LEPR- HSCs did not show age-associated functional impairment at the ages tested. This suggested that subsets of HSCs are susceptible to age-related decline in function at varying ages and that LEPR+ HSCs are a potential target for early cellular therapeutic interventions in delaying the detrimental effects of aging in hematopoiesis.
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Project description:Aging leads to a decline in function of hematopoietic stem cells (HSCs) and increases susceptibility to hematological disease. We found CD61 to be highly expressed in aged HSCs. Here we investigate the role of CD61 in identifying distinct subpopulations of aged HSCs and assess how expression of CD61 affects stem cell function. We show that HSCs with high expression of CD61 are functionality superior and retain self-renewal capacity in serial transplantations. A population of aged HSCs with highest CD61 expression is functionally comparable to young HSCs. These CD61High HSCs display a notably higher quiescence compared to their CD61Low counterparts. We also show that CD61High and CD61Low HSCs are transcriptomically distinct populations within aged HSCs. Collectively, our research identifies CD61 as a key player in maintaining stem cell quiescence during aging, ensuring the preservation of their functional integrity and potential. Moreover, CD61 emerges as a marker to prospectively isolate a superior, highly dormant population of young and aged HSCs, making it a valuable tool both in fundamental and clinical research.
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Project description:Cellular senescence is a stable proliferation arrest that suppresses tumorigenesis. Histone chaperone HIRA deposits nucleosome-destabilizing histone variant H3.3 into chromatin in a DNA replication-independent manner. Histone H3.3 and a subset of other typically M-bM-^@M-^\replication-dependentM-bM-^@M-^] core histones were expressed in non-proliferating senescent cells, the latter linked to alternative mRNA splicing and polyadenylation. Senescent cells incorporated newly-synthesized histones into chromatin, partially dependent on HIRA. HIRA and newly-deposited histone H3.3 co-localized at promoters of expressed genes, and their distribution shifted between proliferating and senescent cells, paralleling changes in gene expression. In senescent cells, gene promoters showed exceptional enrichment of a histone acetylation linked to open and dynamic chromatin, H4K16ac. Abundance of H4K16ac depended on HIRA. In the mouse, inactivation of HIRA downregulated H4K16ac and dramatically enhanced oncogene-induced hyperplasia. To conclude, HIRA controls a previously undefined dynamic non-canonical H4K16ac-decorated chromatin landscape in senescence, and also plays an unanticipated role in suppression of oncogene-induced neoplasia. Examination of HIRA protein binding alongside histone modification H4K16ac and H3.3 in proliferating and senescent IMR90 cells
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Project description:Hematopoietic aging is associated with decreased hematopoietic stem cell (HSC) self-renewal capacity and increased risk for myelodysplasia and leukemia. Deficient DNA repair contributes to the decline in HSC self-renewal capacity during aging and it remains unclear whether extrinsic signals can rejuvenate aged HSCs. Here, we demonstrate that augmentation of non-homologous end-joining (NHEJ) DNA repair in aged HSCs via treatment with epidermal growth factor (EGF) rejuvenates HSC function. Seven day culture of BM CD34-ckit+sca-1+lin- (34-KSL) HSCs from aged C57BL/6 mice with EGF suppressed myeloid skewing and increased production of multipotent CFU-granulocyte, erythroid, monocyte and megakaryocyte (CFU-GEMM) colonies. Aged, EGF-treated HSCs displayed increased donor multilineage engraftment in primary competitively transplanted mice and in secondary mice compared to mice transplanted with aged, control HSCs. Donor cell engraftment within the bone marrow (BM) KSL and SLAM+KSL HSC population was > 2-fold increased in mice transplanted with aged, EGF-treated HSCs. Systemic administration of EGF to aged mice for 6 weeks also increased long term – HSC self-renewal capacity as measured by increased donor bone marrow (BM) competitive repopulation in primary and secondary transplanted mice. Conversely, deletion of EGFR in Scl/Tal1+ hematopoietic cells was associated with increased myeloid skewing and depletion of LT-HSCs in middle aged mice. Mechanistically, EGF treatment decreased DNA damage in aged HSCs through activation of DNA PK-cs, Artemis and NHEJ repair. Inhibition of DNA PK-cs blocked EGF-mediated restoration of multipotent differentiation and suppression of myeloid skewing in aged HSCs, suggesting that the restoration of hematopoietic potential in aged HSCs is dependent on EGF-mediated activation of DNA PK-cs. EGF treatment also converted the transcriptome of aged HSCs from enrichment for genes involved in cell death and survival to genes involved in HSC generation and identity. These data suggest that extrinsic activation of EGFR signaling can restore key functional capacities in aged HSCs.
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Project description:Hematopoietic stem cells (HSCs) exhibit considerable cell-intrinsic changes with age. Here, we performed an integrated analysis of transcriptome and chromatin accessibility of aged HSCs and downstream progenitors. Alterations in chromatin accessibility preferentially took place in HSCs with aging, which gradually resolved with differentiation. Differentially open accessible regions (open DARs) in aged HSCs showed enrichment of binding motifs of the STAT, ATF, and CNC family transcription factors that are activated in response to external stresses, and most of them comprised active, primed , and inactive enhancers. Genes linked to open DARs showed significantly higher levels of basal expression and their expression reached significantly higher peaks after cytokine stimulation in aged HSCs than in young HSCs, suggesting that open DARs contribute to augmented transcriptional responses under stress conditions. These results indicate that the ongoing and/or history of exposure to external stresses is epigenetically inscribed in HSCs to augment their responses to external stimuli.
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Project description:Loss of Phf6 prevents the functional decline and immunophenotypic changes associated with age-related, long-term repopulating hematopoietic stem cell (LT-HSC) exhaustion. To identify the underlying molecular mechanisms that account for these differences, we performed RNA-seq profiling of LT-HSCs isolated from the bone marrow of Phf6 wild-type and knock-out, young (16-week-old) and aged (24-month-old) C57BL/6 mice. Our analysis revealed that LT-HSCs isolated from 24-month-old, Phf6 knockout mice retained the molecular signatures associated with young LT-HSCs whereas LT-HSCs isolated from aged, Phf6 wild-type mice acquired signatures consistent with HSC exhaustion. Mechanistically, these data revealed important roles for key metabolic pathways including glutathione metabolism and sterol biosynthesis, as well as cell-cell interaction and signaling pathways such as the interferon and TGF-beta responses.
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