Abstract
Epigenetic factors (EFs) regulate multiple aspects of cerebral cortex development, including proliferation, differentiation, laminar fate, and regional identity. The same neurodevelopmental processes are also regulated by transcription factors (TFs), notably the Pax6→ Tbr2→ Tbr1 cascade expressed sequentially in radial glial progenitors (RGPs), intermediate progenitors, and postmitotic projection neurons, respectively. Here, we studied the EF landscape and its regulation in embryonic mouse neocortex. Microarray and in situ hybridization assays revealed that many EF genes are expressed in specific cortical cell types, such as intermediate progenitors, or in rostrocaudal gradients. Furthermore, many EF genes are directly bound and transcriptionally regulated by Pax6, Tbr2, or Tbr1, as determined by chromatin immunoprecipitation-sequencing and gene expression analysis of TF mutant cortices. Our analysis demonstrated that Pax6, Tbr2, and Tbr1 form a direct feedforward genetic cascade, with direct feedback repression. Results also revealed that each TF regulates multiple EF genes that control DNA methylation, histone marks, chromatin remodeling, and non-coding RNA. For example, Tbr1 activates Rybp and Auts2 to promote the formation of non-canonical Polycomb repressive complex 1 (PRC1). Also, Pax6, Tbr2, and Tbr1 collectively drive massive changes in the subunit isoform composition of BAF chromatin remodeling complexes during differentiation: for example, a novel switch from Bcl7c (Baf40c) to Bcl7a (Baf40a), the latter directly activated by Tbr2. Of 11 subunits predominantly in neuronal BAF, 7 were transcriptionally activated by Pax6, Tbr2, or Tbr1. Using EFs, Pax6→ Tbr2→ Tbr1 effect persistent changes of gene expression in cell lineages, to propagate features such as regional and laminar identity from progenitors to neurons.
Highlights
Development of the embryonic cerebral cortex is regulated by intrinsic genetic programs and signaling interactions that give rise to diverse cortical areas, layers, and neuron subtypes with distinct gene expression profiles (Sun and Hevner, 2014; Silbereis et al, 2016)
By combining microarray analysis of radial glial progenitors (RGPs) and intermediate progenitors (IPs) transcriptomes (Nelson et al, 2013) with in situ hybridization (ISH) to define gene expression patterns, we find that dozens of Epigenetic factors (EFs) genes exhibit celltype or region-specific expression, and together constitute a rich EF landscape involving all categories of epigenetic mechanisms
Transcriptome profiling and unbiased cluster analysis of single cells indicated that the ventricular zone (VZ) and subventricular zone (SVZ) of E14.5 mouse neocortex contain four cell types: RGPs, apical IPs, basal IPs, and postmitotic projection neurons (PNs) (Kawaguchi et al, 2008)
Summary
Development of the embryonic cerebral cortex is regulated by intrinsic genetic programs and signaling interactions that give rise to diverse cortical areas, layers, and neuron subtypes with distinct gene expression profiles (Sun and Hevner, 2014; Silbereis et al, 2016). Tbr interacts with Jmjd (Gene: Kdm6b), a histone lysine demethylase that removes repressive trimethylation marks on histone H3 lysine 27 (H3K27me3) placed by Polycomb repressive complex 2 (PRC2), to thereby derepress transcription (Sessa et al, 2017) Such interactions illustrate that TFs sometimes function by physically recruiting and targeting EFs to specific genes. Tbr is known to activate Auts (Bedogni et al, 2010a), a Polycomb repressive complex 1 (PRC1) non-canonical subunit (Gao et al, 2014); and Arid1b, an important BAF subunit (Notwell et al, 2016) Building on these few examples, one goal of the present study was to comprehensively identity EF genes that are directly bound and regulated by Pax, Tbr, and Tbr. Our results show how a cortical TF network implements cortical differentiation by controlling diverse EFs
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