An epigenome atlas of neural progenitors within the embryonic mouse forebrain

Abstract

While epigenetic modifications are critical for cell state changes throughout development, a detailed characterization of chromatin accessibility during neurogenesis has not been explored. We collected single-cell chromatin accessibility profiles from four distinct neurogenic regions of the embryonic mouse forebrain using single nuclei ATAC-Seq (snATAC-Seq). We identified thousands of differentially accessible peaks, many restricted to distinct progenitor cell types or brain regions. Integrating snATAC-Seq and transcriptome data, we characterized changes of chromatin accessibility at enhancers and promoters that were tightly coupled to transcript abundance during neurodevelopment. Integrating chromatin accessibility profiles from embryonic and adult interneurons with the iPSYCH2012 dataset revealed several disease-associated polymorphisms overlapped with accessible regions in embryonic cells. These findings highlight a diverse chromatin landscape in embryonic neural progenitors, extensive coordination between chromatin accessibility and gene expression during neuron fate determination, and open the door for future studies to define critical enhancer-promoter interactions that direct cell fate decisions.

Spatial enhancer activation determines inhibitory neuron identity

“…To select enhancers with activity in the developing forebrain, we intersected MEIS1/2-DLX5 co-binding sites from ChIP-seq data with the VISTA in vivo enhancer database (Visel et al, 2007) (Figure S3d). Additionally, we confirmed the accessibility of respective genomic regions utilizing published scATAC-seq data of the LGE and MGE (Rhodes et al, 2022) (Figure 4a). We chose two enhancers (hs1080 and hs956) of the transcription factor Foxp2 , which both contained MEIS/DLX motifs with a spacing of 3 bps (Visel et al, 2007; Visel et al, 2013) (Figure 4a, Figure S4a-c,e).…”

“… a , Representative profiles of MEIS1/2 (red) and DLX5 (blue) ChIP-Seq at E14.5 and E13.5 respectively, as well as scATAC-seq from LGE (dark grey) and MGE (grey) at E12.5 are shown at the Foxp2 gene locus. DLX5 ChIP-Seq data from (Lindtner et al, 2019); scATAC-seq data from (Rhodes et al, 2022). b , Luciferase activity driven by the enhancer hs1080, co-transfected with Meis2 and Dlx5 expression vectors in Neuro2 cells.…”

“… a , b , c , hs1041, hs956, hs748 enhancers drives LacZ expression at E12.5 (Visel et al, 2007). d , e , f , Representative tracks of GE ChIP-Seq of MEIS1/2 at E14.5 (red), DLX5 at E13.5 (blue) (Lindtner et al, 2019), LHX6 at E13.5 (purple) (Sandberg et al, 2016) and scATAC-seq (Rhodes et al, 2022) from the LGE (dark grey) and MGE (grey) at E12.5. g , h , i , Luciferase activity driven by hs1041, hs956, and hs748 enhancers co-transfected with Meis2, Dlx5, and Lhx6 expression vectors in Neuro2a cells.…”

PRDM16 functions as a co-repressor in the BMP pathway to suppress neural stem cell proliferation

“…5B ) and identified 3238 common peaks from three biological replicates. We then manually inspected the 31 gene loci for PRDM16 CUT&TAG peaks pairing with the target gene TSS using the browser Embryonic Mouse Brain Epigenome Atlas (Rhodes et al, 2022). This conformed that most of these genes have at least one PRDM16 binding peak in their promoter-linked enhancers (Text in black, Fig.…”

“…We previously showed that PRDM16 preferentially associates with distal intergenic regions (He et al, 2021), posing a challenge of pairing the PRDM16-bound enhancers to the targeting promoters. To overcome this issue, we took advantage of a public data browser, Embryonic Mouse Brain Epigenome Atlas (Rhodes et al, 2022), where promoterenhancer pairs are predicted by the Monocle3 extension Cicero (Pliner et al, 2018). We manually inspected all 31 genes for the presence of at least one PRDM16 CUT&TAG peak that is associated with the gene promoter, and found that 23 of them have proximal or distal PRDM16 binding peak(s) (Fig.…”