Bone and Joint Rehabilitation R&D Center, VA Palo Alto Medical Center, Palo Alto, CA, United States.
J Biomech. 2010 Nov 16;43(15):2881-6. doi: 10.1016/j.jbiomech.2010.07.033. Epub 2010 Aug 21.
Epigenetic regulation of gene expression occurs due to alterations in chromatin proteins that do not change DNA sequence, but alter the chromatin architecture and the accessibility of genes, resulting in changes to gene expression that are preserved during cell division. Through this process genes are switched on or off in a more durable fashion than other transient mechanisms of gene regulation, such as transcription factors. Thus, epigenetics is central to cellular differentiation and stem cell linage commitment. One such mechanism is DNA methylation, which is associated with gene silencing and is involved in a cell's progression towards a specific fate. Mechanical signals are a crucial regulator of stem cell behavior and important in tissue differentiation; however, there has been no demonstration of a mechanism whereby mechanics can affect gene regulation at the epigenetic level. In this study, we identified candidate DNA methylation sites in the promoter regions of three osteogenic genes from bone marrow derived mesenchymal stem cells (MSCs). We demonstrate that mechanical stimulation alters their epigenetic state by reducing DNA methylation and show an associated increase in expression. We contrast these results with biochemically induced differentiation and distinguish expression changes associated with durable epigenetic regulation from those likely to be due to transient changes in regulation. This is an important advance in stem cell mechanobiology as it is the first demonstration of a mechanism by which the mechanical micro-environment is able to induce epigenetic changes that control osteogenic cell fate, and that can be passed to daughter cells. This is a first step to understanding that will be vital to successful bone tissue engineering and regenerative medicine, where continued expression of a desired long-term phenotype is crucial.
基因表达的表观遗传调控是由于染色质蛋白的改变引起的，这些改变不会改变 DNA 序列，但会改变染色质结构和基因的可及性，导致基因表达的变化，这些变化在细胞分裂过程中得以保留。通过这个过程，基因的开启或关闭比其他瞬时的基因调控机制（如转录因子）更加持久。因此，表观遗传学是细胞分化和干细胞谱系决定的核心。其中一种机制是 DNA 甲基化，它与基因沉默有关，并且参与细胞向特定命运的发展。机械信号是干细胞行为的关键调节剂，在组织分化中很重要；然而，目前还没有证明机械信号可以在表观遗传水平上影响基因调控的机制。在这项研究中，我们从骨髓间充质干细胞（MSCs）中鉴定了三个成骨基因启动子区域的候选 DNA 甲基化位点。我们证明机械刺激通过减少 DNA 甲基化来改变它们的表观遗传状态，并显示出与之相关的表达增加。我们将这些结果与生化诱导的分化进行对比，并区分与持久的表观遗传调控相关的表达变化与可能由于调节的瞬时变化而产生的表达变化。这是干细胞机械生物学的一个重要进展，因为这是第一个证明机械微环境能够诱导控制成骨细胞命运的表观遗传变化的机制，并且这种变化可以传递给子细胞。这是理解的第一步，对于成功的骨组织工程和再生医学至关重要，因为在这些领域中，持续表达所需的长期表型是至关重要的。
