a Department of Biochemistry and Microbiology , University of Victoria , Victoria , BC , V8W 3P6 , Canada.
b Douglas Hospital Research Center , Department of Psychiatry , McGill University , Montréal , Québec H3G 1Y6 , Canada.
Epigenetics. 2017;12(11):934-944. doi: 10.1080/15592294.2017.1380760. Epub 2017 Dec 5.
MeCP2 binds to methylated DNA in a chromatin context and has an important role in cancer and brain development and function. Histone deacetylase (HDAC) inhibitors are currently being used to palliate many cancer and neurological disorders. Yet, the molecular mechanisms involved are not well known for the most part and, in particular, the relationship between histone acetylation and MeCP2 is not well understood. In this paper, we study the effect of the HDAC inhibitor trichostatin A (TSA) on MeCP2, a protein whose dysregulation plays an important role in these diseases. We find that treatment of cells with TSA decreases the phosphorylation state of this protein and appears to result in a higher MeCP2 chromatin binding affinity. Yet, the binding dynamics with which the protein binds to DNA appear not to be significantly affected despite the chromatin reorganization resulting from the high levels of acetylation. HDAC inhibition also results in an overall decrease in MeCP2 levels of different cell lines. Moreover, we show that miR132 increases upon TSA treatment, and is one of the players involved in the observed downregulation of MeCP2.
MECP2 与染色质环境中的甲基化 DNA 结合，在癌症、大脑发育和功能中具有重要作用。组蛋白去乙酰化酶（HDAC）抑制剂目前正被用于缓解许多癌症和神经紊乱。然而，在大多数情况下，其涉及的分子机制并不为人所知，特别是组蛋白乙酰化和 MECP2 之间的关系还没有被很好地理解。在本文中，我们研究了 HDAC 抑制剂曲古抑菌素 A（TSA）对 MECP2 的影响，MECP2 蛋白的失调在这些疾病中起着重要作用。我们发现，用 TSA 处理细胞会降低该蛋白的磷酸化状态，似乎导致其与染色质的结合亲和力增加。然而，尽管由于高水平的乙酰化导致染色质重排，但与 DNA 结合的结合动力学似乎没有受到显著影响。HDAC 抑制也会导致不同细胞系中 MECP2 水平的整体下降。此外，我们还表明，miR132 在 TSA 处理后增加，是观察到的 MECP2 下调的参与者之一。
