Epigenome profiling and editing of neocortical progenitor cells during development. (1st August 2017)

• Record Type: Journal Article
• Authors: Albert, Mareike; Kalebic, Nereo; Florio, Marta; Lakshmanaperumal, Naharajan; Haffner, Christiane; Brandl, Holger; Henry, Ian; Huttner, Wieland B
• Is Part Of: EMBO journal. Volume 36:Number 17(2017)
• Page Start: 2642
• Page End: 2658
• Publication Date: 2017-08-01
• Subjects: Cas9 -- epigenome -- histone methylation -- neocortical development -- neural progenitor cell; Molecular biology -- Periodicals; 572.805
• DOI: 10.15252/embj.201796764
• Languages: English
• ISSNs: 0261-4189

Abstract

Abstract: The generation of neocortical neurons from neural progenitor cells (NPCs) is primarily controlled by transcription factors binding to DNA in the context of chromatin. To understand the complex layer of regulation that orchestrates different NPC types from the same DNA sequence, epigenome maps with cell type resolution are required. Here, we present genomewide histone methylation maps for distinct neural cell populations in the developing mouse neocortex. Using different chromatin features, we identify potential novel regulators of cortical NPCs. Moreover, we identify extensive H3K27me3 changes between NPC subtypes coinciding with major developmental and cell biological transitions. Interestingly, we detect dynamic H3K27me3 changes on promoters of several crucial transcription factors, including the basal progenitor regulator Eomes . We use catalytically inactive Cas9 fused with the histone methyltransferase Ezh2 to edit H3K27me3 at the Eomes locus in vivo, which results in reduced Tbr2 expression and lower basal progenitor abundance, underscoring the relevance of dynamic H3K27me3 changes during neocortex development. Taken together, we provide a rich resource of neocortical histone methylation data and outline an approach to investigate its contribution to the regulation of selected genes during neocortical development. Synopsis: Epigenome maps for distinct neural cell populations in the developing mouse neocortex reveal extensive H3K4me3 and H3K27me3 changes. Editing at the gene encoding transcription factor Eomes suggests that dynamic H3K27me3 changes are required for normal neocortex development. Genome‐wide histone methylation maps with cell type‐resolution identifies potential new regulators in the developing mouse neocortex. Dynamic H3K27me3 changes on promoters of several key neural transcription factors coincide with cell fate transitions. Ezh2 targeting via catalytically inactivate Cas9 enables editing of H3K27me3 in vivo in the developing neocortex. Forced H3K27me3 deposition at the Eomes locus reduces expression of this transcription factor, affecting basal progenitor abundance. Abstract : Mapping genome‐wide histone methylation in distinct mouse neural cell types reveals major changes associated with brain development, while genome editing shows how transient changes in chromatin status can affect regulation of specific genes.