The histone deacetylase complex MiDAC regulates a neurodevelopmental gene expression to control neurite outgrowth [ChIP-Seq]

Cell type diversity during neuro-ectodermal (NE) differentiation is achieved through selective activation and silencing of neurodevelopmental genes. Here, we show a key role for the histone deacetylase complex MiDAC during neuronal differentiation of mouse embryonic stem cells (mESCs) into NE. We demonstrate that MiDAC functions as a modulator of a neurodevelopmental gene expression program and binds to important regulators of neurite outgrowth. MiDAC mediates the removal of H4K20ac on the promoters and enhancers of pro-neural genes such as the axon guidance ligands Slit3 and Ntn1 while in parallel reducing H3K27ac on promoter-proximal and -distal elements of negative regulators of neurogenesis thereby upregulating and inhibiting gene expression, respectively. Furthermore, neurite outgrowth defects in MiDAC KO neurons can be rescued by restoring Slit3/Robo3-Ntn1/Unc5b signaling. Taken together, our work suggests a crucial role for MiDAC in regulating the secretome of the Slit3/Robo3-Ntn1/Unc5b signaling axes to ensure the proper integrity of neurite development. Overall design: ChIP-seq was carried out in mESCs for the histone modification marks H3K4me1, H3K4me3, H3K27ac, H3K27me3 and for Dnttip1, a subunit of MiDAC. ChIPs against each histone mark or Dnttip1 were carried out at least in duplicate for each genotype. Genotypes used were WT, Dnttip1 KO and Elmsan1 KO.