The epigenetic mechanism of mechanically induced osteogenic differentiation.
The epigenetic mechanism of mechanically induced osteogenic differentiation.
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DOI：
10.1016/j.jbiomech.2010.07.033
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发表时间：
2010-11-16
影响因子：
2.4
通讯作者：
Jacobs, Christopher R.
中科院分区：
文献类型：
--
作者：
Arnsdorf, Emily J.;Tummala, Padmaja;Castillo, Alesha B.;Zhang, Fan;Jacobs, Christopher R.
基因表达的表观遗传调控是由于染色质蛋白的改变而发生的，染色质蛋白的改变不改变DNA序列，但改变染色质结构和基因的可接近性，导致细胞分裂期间保留的基因表达发生变化。通过这一过程，基因以比其他瞬时基因调节机制（如转录因子）更持久的方式打开或关闭。因此，表观遗传学是细胞分化和干细胞谱系定型的核心。其中一种机制是DNA甲基化，它与基因沉默有关，并参与细胞向特定命运的进展。机械信号是干细胞行为的关键调节器，在组织分化中很重要，然而，还没有证据表明机械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，我们确定了三个成骨基因的启动子区域的候选DNA甲基化位点从骨髓间充质干细胞（MSCs）。我们证明，机械刺激通过减少DNA甲基化改变了它们的表观遗传状态，并表现出相关的表达增加。我们将这些结果与生化诱导分化进行对比，并将与持久表观遗传调控相关的表达变化与可能是由于调控中的瞬时变化相关的表达变化区分开来。这是干细胞机械生物学的一个重要进展，因为它首次证明了机械微环境能够诱导控制成骨细胞命运的表观遗传变化并可传递给子细胞的机制。这是理解一种机制的第一步，这种机制对成功的骨组织工程和再生医学至关重要，其中持续表达所需的长期表型至关重要。
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 change 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 showed 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 a mechanism that will be vital to successful bone tissue engineering and regenerative medicine where continued expression of a desired long-term phenotype is crucial.
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DOI：
10.1152/ajpcell.2001.281.6.c1917
发表时间：
2001-12-01
影响因子：
5.5
作者：
Saunders, MM;You, J;Jacobs, CR
通讯作者：
Jacobs, CR
影响因子：
4.1
作者：
Kim, Chi Hyun;You, Lidan;Jacobs, Christopher R.
通讯作者：
Jacobs, Christopher R.
影响因子：
4
作者：
Kang, Moo-Il;Kim, Hye-Soo;Rhyu, Mun-Gan
通讯作者：
Rhyu, Mun-Gan
影响因子：
2.8
作者：
Li, YJ;Batra, NN;Jacobs, CR
通讯作者：
Jacobs, CR
影响因子：
3.3
作者：
Noer, Agate;Sorensen, Anita L.;Collas, Philippe
通讯作者：
Collas, Philippe