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Attrition of X chromosome inactivation in aged hematopoietic stem cells

ABSTRACT: During X chromosome inactivation (XCI), the inactive X chromosome (Xi) is recruited to the nuclear lamina at the periphery of the nucleus. Beside X chromosome (X chr) reactivation resulting in a highly penetrant aging-like hematopoietic malignancy, little is known about XCI in aged hematopoietic stem cells (HSCs) . Here, we demonstrate that LaminA/C defines a distinct repressive nuclear compartment for XCI in young HSCs, and its reduction in aged HSCs correlates with an impairment in the overall control of XCI. Integrated omics analyses reveal higher variation in gene expression, global hypomethylation and significantly increased chromatin accessibility on the X chr in aged HSCs. In summary, our data support the role of LaminA/C in the establishment of a special repressive compartment for XCI in HSCs, which is impaired upon aging.

ORGANISM(S): Mus musculus

PROVIDER: GSE167214 | GEO | 2021/04/07

REPOSITORIES: GEO

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LaminA/C regulates epigenetic and chromatin architecture changes upon aging of hematopoietic stem cells

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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single cell RNA sequencing of hematopoietic stem cells aged in old and young niches

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