Institute of Molecular Medicine and Stem Cell Aging, University of Ulm, Albert-Einstein-Allee 11c, 89081 Ulm, Germany.
Section Translational Cancer Epigenomics, Division of Translational Medical Oncology, German Cancer Research Center (DKFZ) & National Center for Tumor Diseases (NCT) Heidelberg, Heidelberg, Germany; Bioinformatics and Omics Data Analysis, German Cancer Research Center (DKFZ), Heidelberg, Germany; Faculty of Biosciences, University of Heidelberg, Heidelberg, Germany; Biomedical Informatics, Data Mining and Data Analytics, Faculty of Applied Computer Science and Medical Faculty, University of Augsburg, Augsburg, Germany.
Stem Cell Reports. 2021 Apr 13;16(4):708-716. doi: 10.1016/j.stemcr.2021.03.007. Epub 2021 Apr 1.
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.
在 X 染色体失活（XCI）过程中，失活的 X 染色体（Xi）被募集到核周的核层。除了导致高穿透性衰老样造血恶性肿瘤的 X 染色体重新激活之外，对于老年造血干细胞（HSCs）中的 XCI 知之甚少。在这里，我们证明 LaminA/C 在年轻的 HSCs 中为 XCI 定义了一个独特的抑制性核区室，并且其在老年 HSCs 中的减少与 XCI 的整体控制受损相关。综合组学分析显示，老年 HSCs 中的基因表达、整体低甲基化和 X 染色体（Chr X）上的染色质可及性显著增加，且变化更大。总之，我们的数据支持 LaminA/C 在 HSCs 中建立 XCI 特殊抑制区室的作用，该作用在衰老时受损。
