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

Genome Biology

Heinrich Leonhardt¹  Yolanda Markaki¹  Christoph Plass²  Yi Zheng³  Christian Buske⁴  Medhanie A. Mulaw⁴  Thomas Liehr⁵  Ani Grigoryan⁶  Katharina Senger⁶  Hartmut Geiger⁶  Angelika Vollmer⁶  Karin Soller⁶  Novella Guidi⁶  Gina Marka⁶  Maria Carolina Florian⁶  Daniel B. Lipka⁷ 

[1] Department of Biology II and Center for Integrated Protein Science Munich (CIPSM), Ludwig Maximilians University Munich;Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ);Division of Experimental Hematology and Cancer Biology, Cincinnati Children’s Hospital Medical Center and University of Cincinnati;Institute of Experimental Cancer Research, Comprehensive Cancer Center Ulm, University Hospital Ulm;Institute of Human Genetics, Jena University Hospital, Friedrich Schiller University;Institute of Molecular Medicine and Stem Cell Aging, University of Ulm;Regulation of Cellular Differentiation Group, INF280;

关键词: Hematopoietic stem cell (HSC);    Aging;    Chromatin architecture;    LaminA/C;    Chromosome 11;   

DOI  :  10.1186/s13059-018-1557-3

来源: DOAJ

【 摘 要 】

Abstract Background The decline of hematopoietic stem cell (HSC) function upon aging contributes to aging-associated immune remodeling and leukemia pathogenesis. Aged HSCs show changes to their epigenome, such as alterations in DNA methylation and histone methylation and acetylation landscapes. We previously showed a correlation between high Cdc42 activity in aged HSCs and the loss of intranuclear epigenetic polarity, or epipolarity, as indicated by the specific distribution of H4K16ac. Results Here, we show that not all histone modifications display a polar localization and that a reduction in H4K16ac amount and loss of epipolarity are specific to aged HSCs. Increasing the levels of H4K16ac is not sufficient to restore polarity in aged HSCs and the restoration of HSC function. The changes in H4K16ac upon aging and rejuvenation of HSCs are correlated with a change in chromosome 11 architecture and alterations in nuclear volume and shape. Surprisingly, by taking advantage of knockout mouse models, we demonstrate that increased Cdc42 activity levels correlate with the repression of the nuclear envelope protein LaminA/C, which controls chromosome 11 distribution, H4K16ac polarity, and nuclear volume and shape in aged HSCs. Conclusions Collectively, our data show that chromatin architecture changes in aged stem cells are reversible by decreasing the levels of Cdc42 activity, revealing an unanticipated way to pharmacologically target LaminA/C expression and revert alterations of the epigenetic architecture in aged HSCs.

【 授权许可】

Unknown