Osteogenic differentiation of human MSCs: Specific occupancy of the mitochondrial DNA by NFATc1 transcription factor
Osteogenic differentiation of human MSCs: Specific occupancy of the mitochondrial DNA by NFATc1 transcription factor
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DOI：
10.1016/j.biocel.2015.04.011
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发表时间：
2015-07-01
影响因子：
4
通讯作者：
Piva, Roberta
中科院分区：
文献类型：
--
作者：
Lambertini, Elisabetta;Penolazzi, Letizia;Piva, Roberta
大量证据表明，线粒体形态和功能在成骨分化过程中发生变化。然而，线粒体动力学与成骨细胞功能调控的分子机制知之甚少。在影响人类间充质干细胞（hMSC）成为成骨细胞的决定的分子中，有Slug和NFATc 1转录因子（TF）。这些分子还干扰不同的ESTA依赖性途径，以响应各种细胞的需求。本研究探讨了成骨分化hMSCs中Slug和NFATc 1在线粒体DNA（mtDNA）D-loop调控区的募集情况，目的是探讨Slug和NFATc 1是否也作为线粒体转录因子在线粒体核转录因子库中发挥作用，结果表明NFATc 1而非Slug定位于线粒体。使用染色质免疫沉淀分析，我们发现NFATc 1在mtDNA中被募集，但这仅发生在骨诱导MSC中钙化过程达到最高水平并达到最大分化水平时。线粒体DNA被NFATc 1占据与关键线粒体基因如细胞色素B和NADH脱氢酶1的表达降低相关。这表明，NFATc 1作为一个负调节器的线粒体DNA转录过程中的钙化过程和中断有氧energydemands.The发现NFATc 1参与成骨分化，通过其直接参与线粒体的监管机制，这TF的一个新的角色，并增加了线粒体和核基因组之间的通信信息。(C)2015爱思唯尔有限公司版权所有。
A substantial body of evidence indicates that mitochondrial morphology and function change during osteogenic differentiation. However, molecular mechanisms linking mitochondrial dynamics with the regulation of osteoblast functions are poorly understood. Amongst the molecules that influence the decision of human mesenchymal stem cells (hMSCs) to become osteoblasts are Slug and NFATc1 transcription factors (TFs). These molecules also interfere with different mitochondria-dependent pathways in response to a variety of cellular demands. The present study investigated the recruitment of Slug and NFATc1 at the D-loop regulatory region of mitochondrial DNA (mtDNA) in osteogenic differentiated hMSCs with the aim of exploring whether Slug and NFATc1 also act as mitoTFs in the mitochondrial pool of nuclear TFs.The results demonstrate that NFATc1, but not Slug, is localized in the mitochondria. Using chromatin immunoprecipitation assay, we found that NFATc1 is recruited at mtDNA, but this occurs only when the calcification process is at its highest in osteo-induced MSC and the maximum level of differentiation is reached. Occupancy of the mtDNA by NFATc1 is associated with a decreased expression of crucial mitochondrial genes such as Cytochrome B and NADH dehydrogenase 1. This suggests that NFATc1 acts as a negative regulator of mtDNA transcription during the calcification process and interruption of aerobic energy demand.The finding of NFATc1 participation in osteogenic differentiation through its direct involvement in the regulatory machinery of mitochondria suggests a new role for this TF and adds information on communication between mitochondrial and nuclear genomes. (C) 2015 Elsevier Ltd. All rights reserved.