Department of Cell & Molecular Biology, St. Jude Children's Research Hospital, Memphis, United States.
Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, United States.
Elife. 2020 Apr 16;9:e57519. doi: 10.7554/eLife.57519.
The mitotic deacetylase complex (MiDAC) is a recently identified histone deacetylase (HDAC) complex. While other HDAC complexes have been implicated in neurogenesis, the physiological role of MiDAC remains unknown. Here, we show that MiDAC constitutes an important regulator of neural differentiation. We demonstrate that MiDAC functions as a modulator of a neurodevelopmental gene expression program and binds to important regulators of neurite outgrowth. MiDAC upregulates gene expression of pro-neural genes such as those encoding the secreted ligands SLIT3 and NETRIN1 (NTN1) by a mechanism suggestive of H4K20ac removal on promoters and enhancers. Conversely, MiDAC inhibits gene expression by reducing H3K27ac on promoter-proximal and -distal elements of negative regulators of neurogenesis. Furthermore, loss of MiDAC results in neurite outgrowth defects that can be rescued by supplementation with SLIT3 and/or NTN1. These findings indicate a crucial role for MiDAC in regulating the ligands of the SLIT3 and NTN1 signaling axes to ensure the proper integrity of neurite development.
有丝分裂去乙酰化酶复合物(MiDAC)是最近发现的组蛋白去乙酰化酶(HDAC)复合物。虽然其他 HDAC 复合物已被牵连到神经发生中,但 MiDAC 的生理作用仍然未知。在这里,我们表明 MiDAC 是神经分化的重要调节因子。我们证明 MiDAC 作为神经发育基因表达程序的调节剂发挥作用,并与神经突生长的重要调节剂结合。MiDAC 通过一种暗示在启动子和增强子上 H4K20ac 去除的机制,上调神经前体细胞基因的表达,例如编码分泌配体 SLIT3 和 NETRIN1(NTN1)的基因。相反,MiDAC 通过减少神经发生负调节剂的启动子近端和远端元件上的 H3K27ac 来抑制基因表达。此外,MiDAC 的缺失导致神经突生长缺陷,可通过补充 SLIT3 和/或 NTN1 来挽救。这些发现表明 MiDAC 在调节 SLIT3 和 NTN1 信号轴的配体方面起着至关重要的作用,以确保神经突发育的适当完整性。