高胆固醇血症通过 Tet1 依赖途径加速造血干细胞的衰老表型。
Hypercholesterolemia Accelerates the Aging Phenotypes of Hematopoietic Stem Cells by a Tet1-Dependent Pathway.
机构信息
Division of Vascular and Endovascular Surgery, University of Massachusetts Medical School, Worcester, MA, 01655, USA.
Diabetes Center of Excellence and Division of Vascular and Endovascular Surgery, University of Massachusetts Medical School, Worcester, MA, 01655, USA.
出版信息
Sci Rep. 2020 Feb 27;10(1):3567. doi: 10.1038/s41598-020-60403-w.
Hypercholesterolemia accelerates the phenotypes of aging in hematopoietic stem cells (HSCs). As yet, little is known about the underlying mechanism. We found that hypercholesterolemia downregulates Ten eleven translocation 1 (Tet1) in HSCs. The total HSC population was increased, while the long-term (LT) population, side population and reconstitution capacity of HSCs were significantly decreased in Tet1 mice. Expression of the Tet1 catalytic domain in HSCs effectively restored the LT population and reconstitution capacity of HSCs isolated from Tet1 mice. While Tet1 deficiency upregulated the expression of p19 and p21 in HSCs by decreasing the H3K27me3 modification, the restoration of Tet1 activity reduced the expression of p19, p21 and p27 by restoring the H3K27me3 and H3K36me3 modifications on these genes. These results indicate that Tet1 plays a critical role in maintaining the quiescence and reconstitution capacity of HSCs and that hypercholesterolemia accelerates HSC aging phenotypes by decreasing Tet1 expression in HSCs.
高胆固醇血症加速造血干细胞（HSCs）的衰老表型。然而，其潜在机制知之甚少。我们发现高胆固醇血症下调了 HSCs 中的 Ten eleven translocation 1（Tet1）。Tet1 小鼠的总 HSC 群体增加，而 LT 群体、侧群和 HSCs 的重建能力则显著降低。在 HSCs 中表达 Tet1 的催化结构域可有效恢复 Tet1 小鼠分离的 LT 群体和重建能力。虽然 Tet1 缺失通过降低 H3K27me3 修饰而上调 HSCs 中 p19 和 p21 的表达，但 Tet1 活性的恢复通过恢复这些基因上的 H3K27me3 和 H3K36me3 修饰来降低 p19、p21 和 p27 的表达。这些结果表明 Tet1 在维持 HSCs 的静止和重建能力方面起着关键作用，而高胆固醇血症通过降低 HSCs 中的 Tet1 表达加速 HSC 衰老表型。
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