Attrition of X Chromosome Inactivation in Aged Hematopoietic Stem Cells

During X chromosome inactivation (XCI), the inactive X chromosome (Xi) is recruited to the nuclear lamina at the nuclear periphery. Beside X chromosome reactivation resulting in a highly penetrant aging-like hematopoietic malignancy, little is known about XCI in aged hematopoietic stem cells (HSCs)....

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Published in:Stem cell reports 2021-04, Vol.16 (4), p.708-716
Main Authors: Grigoryan, Ani, Pospiech, Johannes, Krämer, Stephen, Lipka, Daniel, Liehr, Thomas, Geiger, Hartmut, Kimura, Hiroshi, Mulaw, Medhanie A., Florian, Maria Carolina
Format: Article
Language:English
Subjects:
aging
Animals
ATACseq
Cellular Senescence - genetics
Chromatin - metabolism
chromatin accessibility
chromatin architecture
Chromatin Immunoprecipitation Sequencing
hematopoietic stem cell
Hematopoietic Stem Cells - metabolism
HSC
Humans
Lamin Type A - metabolism
LaminA/C
Mice
Mice, Inbred C57BL
scRNAseq
Transposases - metabolism
X Chromosome - genetics
X chromosome inactivation
X Chromosome Inactivation - genetics
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Summary:During X chromosome inactivation (XCI), the inactive X chromosome (Xi) is recruited to the nuclear lamina at the nuclear periphery. Beside X chromosome 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 chromosome (Chr X) 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. [Display omitted] •Xist lncRNA expression is reduced in HSCs upon aging•The inactive Chr X is distant from the repressive nuclear periphery in aged HSCs•The inactive Chr X is located at the LaminA/C pole in young HSCs•Chromatin accessibility on the X chromosome is increased in aged HSCs In this article, Mulaw, Florian and colleagues show that LaminA/C reduction in aged HSCs correlates with an impairment in X chromosome inactivation (XCI) in aged hematopoietic stem cells (HSCs). Consistently, integrated omics analyses reveal higher variation in gene expression, global hypomethylation, and significantly increased chromatin accessibility on the X chromosome (Chr X) in aged stem cells.
ISSN:2213-6711
2213-6711
DOI:10.1016/j.stemcr.2021.03.007