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Genome Biol. 2018 Nov 7;19(1):189. doi: 10.1186/s13059-018-1557-3.

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

Author information

1
Institute of Molecular Medicine and Stem Cell Aging, University of Ulm, Albert-Einstein-Allee 11c, 89081, Ulm, Germany.
2
Institute of Human Genetics, Jena University Hospital, Friedrich Schiller University, Kollegiengasse 10, 07743, Jena, Germany.
3
Department of Biology II and Center for Integrated Protein Science Munich (CIPSM), Ludwig Maximilians University Munich, Großhaderner Strasse 2, 82152, Planegg-Martinsried, Germany.
4
Institute of Experimental Cancer Research, Comprehensive Cancer Center Ulm, University Hospital Ulm, Albert-Einstein-Allee 11, 89081, Ulm, Germany.
5
Regulation of Cellular Differentiation Group, INF280, 69120, Heidelberg, Germany.
6
Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ), INF280, 69120, Heidelberg, Germany.
7
Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center and University of Cincinnati, Cincinnati, OH, USA.
8
Institute of Molecular Medicine and Stem Cell Aging, University of Ulm, Albert-Einstein-Allee 11c, 89081, Ulm, Germany. carolina.florian@uni-ulm.de.
9
Center of Regenerative Medicine in Barcelona (CMRB), Hospital Duran i Reynals, Gran Via de l'Hospitalet, 199-203, L'Hospitalet de Llobregat, 08908, Barcelona, Spain. carolina.florian@uni-ulm.de.

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.

KEYWORDS:

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

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