Histone H3 Acetylation at Sox1ot Promoter by Targeted Epigenome Editing Augments Proliferation of Intermediate Progenitors in Developing Cortex

Factors regulating the genesis and expansion of basal progenitor cell sub-populations, including intermediate progenitor cells, are critical determinants of cortical neurogenesis and brain growth. Epigenetic (chromatin) marks have emerged as notable regulators of cortical development. However, it is unclear how these factors specifically interact in the epigenome to orchestrate brain development. Here, we combined in vivo electroporation and a CRISPR-dead (d)Cas9 system to probe the contribution of a specific histone modification mark, H3K9ac (H3K9 acetylation), in the epigenome of isolated intermediate progenitor cells in developing mouse cortices. CRISPR-dCas9-mediated addition of H3K9ac at the promoter region of lncRNA Sox1ot resulted in Sox1ot upregulation, with attendant increase in the intermediate progenitor pool and augmented neurogenesis. Thus, we found an interplay between H3K9ac and Sox1ot, which drives the amplification of cortical intermediate progenitor cell population. By targeting H3K9ac to the Sox1ot promoter, we were able to stimulate the proliferation of intermediate progenitor cells leading to enhanced cortical neurogenesis. In essence, we have identified H3K9ac as a key epigenetic regulator of Sox1ot expression, which may dynamically be involved in intermediate progenitor cell pool expansion during brain development and evolution.