Histone deacetylase 2 (HDAC2) is a major HDAC protein in the adult brain and has been shown to regulate many neuronal genes. Aberrant expression of HDAC2 and subsequent dysregulation of neuronal gene expression is implicated in neurodegeneration and brain aging. Human induced pluripotent stem cell-derived neurons (hiPSC-Ns) are widely used models for studying neurodegenerative disease mechanisms, but the role of HDAC2 in hiPSC-N differentiation and maturation has not been explored. In this study, we show that levels of HDAC2 progressively decrease as hiPSCs are differentiated towards neurons. This suppression of HDAC2 inversely corresponds to an increase in neuron-specific isoforms of Endophilin-B1, a multifunctional protein involved in mitochondrial dynamics. Expression of neuron-specific isoforms of Endophilin-B1 is accompanied by concomitant expression of a neuron-specific alternative splicing factor, SRRM4. Manipulation of HDAC2 and Endophilin-B1 using lentiviral approaches shows that knock-down of HDAC2 or overexpression of a neuron-specific Endophilin-B1 isoform promotes mitochondrial elongation and protects against cytotoxic stress in hiPSC-Ns, while HDAC2 knock-down specifically influences genes regulating mitochondrial dynamics and synaptogenesis. Furthermore, HDAC2 knock-down promotes enhanced mitochondrial respiration and reduces levels of neurotoxic amyloid beta peptides. Collectively, our study demonstrates a role for HDAC2 in hiPSC-neuronal differentiation, highlights neuron-specific isoforms of Endophilin-B1 as a marker of differentiating hiPSC-Ns, and demonstrates that HDAC2 regulates key neuronal and mitochondrial pathways in hiPSC-Ns.

中文翻译：

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人类诱导的多能干细胞衍生神经元中HDAC2表达的减少可改善神经元成熟，线粒体动力学和细胞神经退行性疾病表型。

组蛋白脱乙酰基酶2（HDAC2）是成人大脑中的主要HDAC蛋白，已被证明可调节许多神经元基因。HDAC2的异常表达和随后的神经元基因表达失调与神经变性和脑衰老有关。人类诱导的多能干细胞源神经元（hiPSC-Ns）被广泛用于研究神经退行性疾病的机制，但尚未探索HDAC2在hiPSC-N分化和成熟中的作用。在这项研究中，我们表明，随着hiPSC向神经元的分化，HDAC2的水平逐渐降低。HDAC2的这种抑制反过来对应于Endophilin-B1（一种参与线粒体动力学的多功能蛋白）的神经元特异性同工型的增加。Endophilin-B1的神经元特异性同工型的表达伴随着神经元特异性替代剪接因子SRRM4的同时表达。使用慢病毒方法处理HDAC2和Endophilin-B1显示，敲除HDAC2或过度表达神经元特异性Endophilin-B1亚型可促进线粒体伸长，并防止hiPSC-Ns中的细胞毒性应激，而HDAC2敲除可特异性影响调节基因的基因线粒体动力学和突触形成。此外，HDAC2敲低促进线粒体呼吸增强，并降低神经毒性淀粉样β肽的水平。总的来说，我们的研究证明了HDAC2在hiPSC神经元分化中的作用，强调了Endophilin-B1的神经元特异性同工型可作为区分hiPSC-Ns的标记，