A High-Resolution Enhancer Atlas of the Developing Telencephalon

U.S. Department of Energy Joint Genome Institute, Walnut Creek, CA 94598, USA. Electronic address: .
Cell (Impact Factor: 32.24). 01/2013; 152(4). DOI: 10.1016/j.cell.2012.12.041
Source: PubMed


The mammalian telencephalon plays critical roles in cognition, motor function, and emotion. Though 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 more than 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 more than 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.

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    • "Strong overlap was found between the data sets described here and those previously analyzed for seven distinct brain regions (Zhu et al., 2013), as 96% of the enhancers recovered in that study was also found in the larger data set presented here. For p300 data generated from a single human fetal cortex (Visel et al., 2013), 67% was found back in these data sets. The latter was expected to be more divergent, as it involves the comparison between adult and fetal stages for which significant differences in gene expression patterns are also found (Colantuoni et al., 2011; Kang et al., 2011). "
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    ABSTRACT: Understanding the complexity of the human brain and its functional diversity remain a major challenge. Distinct anatomical regions are involved in an array of processes, including organismal homeostasis, cognitive functions, and susceptibility to neurological pathologies, many of which define our species. Distal enhancers have emerged as key regulatory elements that acquire histone modifications in a cell- and species-specific manner, thus enforcing specific gene expression programs. Here, we survey the epigenomic landscape of promoters and cis-regulatory elements in 136 regions of the adult human brain. We identify a total of 83,553 promoter-distal H3K27ac-enriched regions showing global characteristics of brain enhancers. We use coregulation of enhancer elements across many distinct regions of the brain to uncover functionally distinct networks at high resolution and link these networks to specific neuroglial functions. Furthermore, we use these data to understand the relevance of noncoding genomic variations previously linked to Parkinson's disease incidence.
    Cell Reports 10/2014; 9(2):767-79. DOI:10.1016/j.celrep.2014.09.023 · 8.36 Impact Factor
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    • "3 of 29 Research article mammalian non-coding regions serve as developmental limb and nervous system enhancers (Pennacchio et al., 2006). In contrast, other tissues including the heart (Blow et al., 2010; May et al., 2012), liver (Kim et al., 2011), and adult brain (Visel et al., 2013) possess many functional enhancers that do not show such deep phylogenetic preservation at the DNA level. An increasingly used way to identify tissue and species-specific gene regulatory regions is to compare experimentally determined TF–DNA interactions or histone modifications between species (Kunarso et al., 2010; Mikkelsen et al., 2010; Schmidt et al., 2010, 2012; Xiao et al., 2012; Cotney et al., 2013; Paris et al., 2013). "
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    ABSTRACT: As exome sequencing gives way to genome sequencing, the need to interpret the function of regulatory DNA becomes increasingly important. To test whether evolutionary conservation of cis-regulatory modules (CRMs) gives insight into human gene regulation, we determined transcription factor (TF) binding locations of four liver-essential TFs in liver tissue from human, macaque, mouse, rat, and dog. Approximately, two thirds of the TF-bound regions fell into CRMs. Less than half of the human CRMs were found as a CRM in the orthologous region of a second species. Shared CRMs were associated with liver pathways and disease loci identified by genome-wide association studies. Recurrent rare human disease causing mutations at the promoters of several blood coagulation and lipid metabolism genes were also identified within CRMs shared in multiple species. This suggests that multi-species analyses of experimentally determined combinatorial TF binding will help identify genomic regions critical for tissue-specific gene control. DOI:
    eLife Sciences 10/2014; 3. DOI:10.7554/eLife.02626 · 9.32 Impact Factor
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    • "In the developing neocortex (Estará s et al., 2012; Visel et al., 2013), we found that 59% of the mapped enhancers exhibited JMJD3 enrichment. Notably, these enhancers corresponded strongly to neuron differentiation, forebrain development , regulation of neurogenesis, and other activities consistent with NSC differentiation and cortical development. "
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    ABSTRACT: The epigenetic mechanisms that enable lifelong neurogenesis from neural stem cells (NSCs) in the adult mammalian brain are poorly understood. Here, we show that JMJD3, a histone H3 lysine 27 (H3K27) demethylase, acts as a critical activator of neurogenesis from adult subventricular zone (SVZ) NSCs. JMJD3 is upregulated in neuroblasts, and Jmjd3 deletion targeted to SVZ NSCs in both developing and adult mice impairs neuronal differentiation. JMJD3 regulates neurogenic gene expression via interaction at not only promoter regions but also neurogenic enhancer elements. JMJD3 localizes at neural enhancers genome-wide in embryonic brain, and in SVZ NSCs, JMJD3 regulates the I12b enhancer of Dlx2. In Jmjd3-deleted SVZ cells, I12b remains enriched with H3K27me3 and Dlx2-dependent neurogenesis fails. These findings support a model in which JMJD3 and the poised state of key transcriptional regulatory elements comprise an epigenetic mechanism that enables the activation of neurogenic gene expression in adult NSCs throughout life.
    Cell Reports 08/2014; 8(5). DOI:10.1016/j.celrep.2014.07.060 · 8.36 Impact Factor
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