X chromosome in aged hematopoietic stem cells (HSC)

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 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 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.

在X染色体失活（X chromosome inactivation, XCI）过程中，失活X染色体（inactive X chromosome, Xi）会被招募至细胞核外周的核纤层。目前学界对衰老造血干细胞（hematopoietic stem cells, HSCs）中的XCI机制所知甚少，仅明确X染色体再激活可引发高外显率的类衰老造血系统恶性肿瘤。本研究证实，核纤层蛋白A/C（LaminA/C）可在年轻造血干细胞中构建出介导XCI的独特抑制性核区室；而衰老造血干细胞内LaminA/C的表达下调，与XCI的整体调控缺陷显著相关。整合组学分析显示，衰老造血干细胞的X染色体上存在更高水平的基因表达变异、整体低甲基化状态，以及显著升高的染色质可及性。综上，本研究数据证实，LaminA/C在造血干细胞中参与构建XCI所需的特异性抑制性核区室，该结构的功能会在衰老过程中受损。