A High-Resolution Enhancer Atlas of the Developing Telencephalon

Abstract

Summary The mammalian telencephalon plays critical roles in cognition, motor function, and emotion. While many of the genes required for its development have been identified, the distant-acting regulatory sequences orchestrating their in vivo expression are mostly unknown. Here we describe a digital atlas of in vivo enhancers active in subregions of the developing telencephalon. We identified over 4,600 candidate embryonic forebrain enhancers and studied the in vivo activity of 329 of these sequences in transgenic mouse embryos. We generated serial sets of histological brain sections for 145 reproducible forebrain enhancers, resulting in a publicly accessible web-based data collection comprising over 32,000 sections. We also used epigenomic analysis of human and mouse cortex tissue to directly compare the genome-wide enhancer architecture in these species. These data provide a primary resource for investigating gene regulatory mechanisms of telencephalon development and enable studies of the role of distant-acting enhancers in neurodevelopmental disorders.

Genome-Wide Prediction and Validation of Intergenic Enhancers in Arabidopsis Using Open Chromatin Signatures

“…Only 21 of these were found in all three tissues (Visel et al, 2009). A similar specificity was observed for mammalian enhancers developed in several other tissues (Blow et al, 2010;Visel et al, 2013).…”

BAC transgenic zebrafish reveal hypothalamic enhancer activity around obesity associated SNP rs9939609 within the human FTO gene

“…This is no proof, but from our enhancer detection screen and another transposon‐based enhancer detection approach we find that enhancer activity decreases with increasing distance from the gene (Kikuta et al ., 2007b; Kokubu et al ., 2009). Other support for this notion comes from p300 and H3K27ac ChIP sequencing data produced in embryonic and fetal mouse forebrain (Visel et al ., 2013). These data do not reveal active enhancers in intron 2 and 3, but in intron 1.…”

Functional and topological characteristics of mammalian regulatory domains

“…Importantly, since the regulatory sensor is driven by the same promoter at each insertion site, changes in expression are not due to differently responsive promoters, but really outline the limits of enhancer action. We cannot formally exclude that co-expression of the sensor at different positions results from activation by different enhancers with overlapping activities, like those discovered around developmental genes (Carvajal et al 2001;Uchikawa et al 2003;Hong et al 2008;Marini c et al 2013;Visel et al 2013). But individual enhancers usually have distinct spatial activities (Visel et al 2007) and therefore, the spatially restricted expression patterns that we use to define co-expression provide confidence for genuine co-regulation.…”

“…It may help specify gene-enhancer interactions, and restrict ectopic ''enhancer adoption'' to accidental disruption of existing topologies, for example, through chromosomal rearrangements (Kokubu et al 2003;Spitz et al 2003;Niedermaier et al 2005;Gostissa et al 2009;Kantaputra et al 2010;Marini c et al 2013). Alternatively, it may help integrate the activity of multiple regulatory elements spread along large intervals (Carvajal et al 2001;Uchikawa et al 2003;Montavon et al 2011;Li et al 2012;Sanyal et al 2012;Shen et al 2012;Delpretti et al 2013;Marini c et al 2013;Visel et al 2013) into the coherent regulatory units that have been described as regulatory archipelagos, holo-enhancers or chromatin-hubs (Palstra et al 2003;Montavon et al 2011;Marini c et al 2013). Our observation that in intact endogenous loci, randomly inserted sensors report the complete integrated output provided to normal target genes (and do not decompose it into the individual activities of the closest enhancers) (e.g., Hoxd, Supplemental Fig.…”