Data_Sheet_8_Tau Stabilizes Chromatin Compaction.PDF

An extensive body of literature suggested a possible role of the microtubule-associated protein Tau in chromatin functions and/or organization in neuronal, non-neuronal, and cancer cells. How Tau functions in these processes remains elusive. Here we report that Tau expression in breast cancer cell lines causes resistance to the anti-cancer effects of histone deacetylase inhibitors, by preventing histone deacetylase inhibitor-inducible gene expression and remodeling of chromatin structure. We identify Tau as a protein recognizing and binding to core histone when H3 and H4 are devoid of any post-translational modifications or acetylated H4 that increases the Tau’s affinity. Consistent with chromatin structure alterations in neurons found in frontotemporal lobar degeneration, Tau mutations did not prevent histone deacetylase-inhibitor-induced higher chromatin structure remodeling by suppressing Tau binding to histones. In addition, we demonstrate that the interaction between Tau and histones prevents further histone H3 post-translational modifications induced by histone deacetylase-inhibitor treatment by maintaining a more compact chromatin structure. Altogether, these results highlight a new cellular role for Tau as a chromatin reader, which opens new therapeutic avenues to exploit Tau biology in neuronal and cancer cells.

已有大量研究文献表明，微管相关蛋白Tau（microtubule-associated protein Tau）在神经元、非神经元及癌细胞的染色质功能和/或染色质组织中可能发挥一定作用。目前Tau在上述过程中的具体作用机制仍未阐明。本研究发现，乳腺癌细胞系中Tau的表达可通过阻断组蛋白去乙酰化酶抑制剂（histone deacetylase inhibitors）诱导的基因表达与染色质结构重塑，使癌细胞对组蛋白去乙酰化酶抑制剂的抗癌效应产生耐药性。我们证实，当组蛋白H3（histone H3）与组蛋白H4（histone H4）未发生任何翻译后修饰（post-translational modifications），或组蛋白H4发生乙酰化时，Tau可作为识别并结合核心组蛋白的蛋白，且乙酰化H4可增强Tau与组蛋白的结合亲和力。与额颞叶变性（frontotemporal lobar degeneration）患者神经元中观察到的染色质结构改变相一致，Tau突变可通过削弱Tau与组蛋白的结合能力，无法阻断组蛋白去乙酰化酶抑制剂诱导的染色质高级结构重塑。此外，我们证明，Tau与组蛋白的相互作用可通过维持更为紧密的染色质结构，抑制组蛋白去乙酰化酶抑制剂处理后进一步引发的组蛋白H3翻译后修饰。综上，本研究揭示了Tau作为染色质阅读器（chromatin reader）的全新细胞功能，为在神经元及癌细胞中靶向调控Tau的生物学特性开辟了新的治疗途径。