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• W2060316084 abstract "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. 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. Genome-wide screen identifies distant-acting enhancers in the developing forebrain High-resolution mapping shows in vivo enhancer activities in transgenic mice Computational analysis provides sequence classifiers for telencephalon subregions Comparison of human and mouse cortex reveals differences in enhancer architecture The telencephalon houses the cerebral cortex and basal ganglia, structures that are pivotal for human brain functions (Wilson and Rubenstein, 2000Wilson S.W. Rubenstein J.L. Induction and dorsoventral patterning of the telencephalon.Neuron. 2000; 28: 641-651Abstract Full Text Full Text PDF PubMed Scopus (247) Google Scholar). Impaired telencephalic development and function are associated with major neurological and neuropsychiatric disorders, including mental deficiency, cerebral palsy, epilepsy, schizophrenia, and autism (Lewis and Sweet, 2009Lewis D.A. Sweet R.A. Schizophrenia from a neural circuitry perspective: advancing toward rational pharmacological therapies.J. Clin. Invest. 2009; 119: 706-716Crossref PubMed Scopus (180) Google Scholar; Walsh et al., 2008aWalsh C.A. Morrow E.M. Rubenstein J.L. Autism and brain development.Cell. 2008; 135: 396-400Abstract Full Text Full Text PDF PubMed Scopus (138) Google Scholar). Significant progress has been made toward defining spatially resolved gene expression patterns in the developing and adult brains of mouse and human on a genomic scale (Diez-Roux et al., 2011Diez-Roux G. Banfi S. Sultan M. Geffers L. Anand S. Rozado D. Magen A. Canidio E. Pagani M. Peluso I. et al.A high-resolution anatomical atlas of the transcriptome in the mouse embryo.PLoS Biol. 2011; 9: e1000582Crossref PubMed Scopus (459) Google Scholar; Gong et al., 2003Gong S. Zheng C. Doughty M.L. Losos K. Didkovsky N. Schambra U.B. Nowak N.J. Joyner A. Leblanc G. Hatten M.E. Heintz N. A gene expression atlas of the central nervous system based on bacterial artificial chromosomes.Nature. 2003; 425: 917-925Crossref PubMed Scopus (1599) Google Scholar; Gray et al., 2004Gray P.A. Fu H. Luo P. Zhao Q. Yu J. Ferrari A. Tenzen T. Yuk D.I. Tsung E.F. Cai Z. et al.Mouse brain organization revealed through direct genome-scale TF expression analysis.Science. 2004; 306: 2255-2257Crossref PubMed Scopus (341) Google Scholar; Lein et al., 2007Lein E.S. Hawrylycz M.J. Ao N. Ayres M. Bensinger A. Bernard A. Boe A.F. Boguski M.S. Brockway K.S. Byrnes E.J. et al.Genome-wide atlas of gene expression in the adult mouse brain.Nature. 2007; 445: 168-176Crossref PubMed Scopus (3669) Google Scholar; Portales-Casamar et al., 2010Portales-Casamar E. Swanson D.J. Liu L. de Leeuw C.N. Banks K.G. Ho Sui S.J. Fulton D.L. Ali J. Amirabbasi M. Arenillas D.J. et al.A regulatory toolbox of MiniPromoters to drive selective expression in the brain.Proc. Natl. Acad. Sci. USA. 2010; 107: 16589-16594Crossref PubMed Scopus (60) Google Scholar; Visel et al., 2004Visel A. Thaller C. Eichele G. GenePaint.org: an atlas of gene expression patterns in the mouse embryo.Nucleic Acids Res. 2004; 32: D552-D556Crossref PubMed Google Scholar; Zeng et al., 2012Zeng H. Shen E.H. Hohmann J.G. Oh S.W. Bernard A. Royall J.J. Glattfelder K.J. Sunkin S.M. Morris J.A. Guillozet-Bongaarts A.L. et al.Large-scale cellular-resolution gene profiling in human neocortex reveals species-specific molecular signatures.Cell. 2012; 149: 483-496Abstract Full Text Full Text PDF PubMed Scopus (221) Google Scholar). In contrast, the distant-acting gene regulatory sequences that are critical for orchestrating the spatial and temporal expression of genes in the developing and adult brain remain poorly defined despite evidence from large-scale human genetic studies demonstrating the contribution of regulatory sequences to a wide spectrum of human traits and disorders (Durbin et al., 2010Durbin R.M. Abecasis G.R. Altshuler D.L. Auton A. Brooks L.D. Gibbs R.A. Hurles M.E. McVean G.A. 1000 Genomes Project ConsortiumA map of human genome variation from population-scale sequencing.Nature. 2010; 467: 1061-1073Crossref PubMed Scopus (5937) Google Scholar; Maurano et al., 2012Maurano M.T. Humbert R. Rynes E. Thurman R.E. Haugen E. Wang H. Reynolds A.P. Sandstrom R. Qu H. Brody J. et al.Systematic localization of common disease-associated variation in regulatory DNA.Science. 2012; 337: 1190-1195Crossref PubMed Scopus (2200) Google Scholar) and anecdotal direct evidence for a critical requirement for enhancers in brain development (Kurokawa et al., 2004Kurokawa D. Takasaki N. Kiyonari H. Nakayama R. Kimura-Yoshida C. Matsuo I. Aizawa S. Regulation of Otx2 expression and its functions in mouse epiblast and anterior neuroectoderm.Development. 2004; 131: 3307-3317Crossref PubMed Scopus (70) Google Scholar; Shim et al., 2012Shim S. Kwan K.Y. Li M. Lefebvre V. Sestan N. Cis-regulatory control of corticospinal system development and evolution.Nature. 2012; 486: 74-79PubMed Google Scholar). Unlike protein-coding genes, enhancers involved in specific biological processes are difficult to identify because they reside in the vast and poorly characterized noncoding portion of the genome and can be located hundreds of thousands of base pairs away from the promoters of the target genes that they regulate (Lettice et al., 2003Lettice L.A. Heaney S.J. Purdie L.A. Li L. de Beer P. Oostra B.A. Goode D. Elgar G. Hill R.E. de Graaff E. A long-range Shh enhancer regulates expression in the developing limb and fin and is associated with preaxial polydactyly.Hum. Mol. Genet. 2003; 12: 1725-1735Crossref PubMed Scopus (818) Google Scholar). The introduction of enhancer prediction methods based on extreme evolutionary conservation (Nobrega et al., 2003Nobrega M.A. Ovcharenko I. Afzal V. Rubin E.M. Scanning human gene deserts for long-range enhancers.Science. 2003; 302: 413Crossref PubMed Scopus (489) Google Scholar; Pennacchio et al., 2006Pennacchio L.A. Ahituv N. Moses A.M. Prabhakar S. Nobrega M.A. Shoukry M. Minovitsky S. Dubchak I. Holt A. Lewis K.D. et al.In vivo enhancer analysis of human conserved non-coding sequences.Nature. 2006; 444: 499-502Crossref PubMed Scopus (875) Google Scholar; Visel et al., 2008Visel A. Prabhakar S. Akiyama J.A. Shoukry M. Lewis K.D. Holt A. Plajzer-Frick I. Afzal V. Rubin E.M. Pennacchio L.A. Ultraconservation identifies a small subset of extremely constrained developmental enhancers.Nat. Genet. 2008; 40: 158-160Crossref PubMed Scopus (244) Google Scholar) and chromatin immunoprecipitation sequencing (ChIP-seq) (Visel et al., 2009aVisel A. Blow M.J. Li Z. Zhang T. Akiyama J.A. Holt A. Plajzer-Frick I. Shoukry M. Wright C. Chen F. et al.ChIP-seq accurately predicts tissue-specific activity of enhancers.Nature. 2009; 457: 854-858Crossref PubMed Scopus (1252) Google Scholar) increased the efficiency of identifying enhancers. Importantly, ChIP-seq experiments that are performed directly on tissues can provide accurate predictions of the broad, general anatomical region in which an enhancer is active (Visel et al., 2009aVisel A. Blow M.J. Li Z. Zhang T. Akiyama J.A. Holt A. Plajzer-Frick I. Shoukry M. Wright C. Chen F. et al.ChIP-seq accurately predicts tissue-specific activity of enhancers.Nature. 2009; 457: 854-858Crossref PubMed Scopus (1252) Google Scholar). Nevertheless, the spatial resolution of these methods is limited, and detailed in vivo studies are required to precisely define the activity patterns of enhancers at high resolution. To address the need for an improved understanding of the cis-regulatory architecture and gene networks active during telencephalic development, we combined sequence conservation- and ChIP-seq-based enhancer prediction with large-scale histological activity analysis of human telencephalon enhancers in transgenic mice. We demonstrate how the high-resolution neuroanatomical annotation of enhancer activities can be used to develop computational sequence classifiers for enhancers active in different subregions of the telencephalon. We also directly compare the genome-wide enhancer architecture active in the mouse and human cortex using ChIP-seq from these tissues, and we provide examples of downstream applications for enhancers identified through this work. To generate a genome-wide set of forebrain enhancer candidate sequences, we collected forebrain tissue from embryonic day 11.5 (e11.5) mouse embryos and performed tissue-ChIP-seq using an antibody for the enhancer-associated protein p300. Results were analyzed alongside previously described data to increase sampling depth (see Extended Experimental Procedures, available online). Genome-wide enrichment analysis led to the identification of 4,425 noncoding regions genome wide that are distal from transcription start sites and significantly enriched in p300 binding in the e11.5 forebrain (Table S1A). Because p300 was previously shown to be associated with active tissue-specific enhancers (Blow et al., 2010Blow M.J. McCulley D.J. Li Z. Zhang T. Akiyama J.A. Holt A. Plajzer-Frick I. Shoukry M. Wright C. Chen F. et al.ChIP-Seq identification of weakly conserved heart enhancers.Nat. Genet. 2010; 42: 806-810Crossref PubMed Scopus (332) Google Scholar; Visel et al., 2009aVisel A. Blow M.J. Li Z. Zhang T. Akiyama J.A. Holt A. Plajzer-Frick I. Shoukry M. Wright C. Chen F. et al.ChIP-seq accurately predicts tissue-specific activity of enhancers.Nature. 2009; 457: 854-858Crossref PubMed Scopus (1252) Google Scholar), these sequences were predicted to be distant-acting forebrain enhancers. As a complementary approach to identifying candidate enhancers, we also used extreme sequence conservation in conjunction with genomic location. Thus, we scrutinized sequences under extreme evolutionary constraint (Siepel et al., 2005Siepel A. Bejerano G. Pedersen J.S. Hinrichs A.S. Hou M. Rosenbloom K. Clawson H. Spieth J. Hillier L.W. Richards S. et al.Evolutionarily conserved elements in vertebrate, insect, worm, and yeast genomes.Genome Res. 2005; 15: 1034-1050Crossref PubMed Scopus (2616) Google Scholar; Visel et al., 2008Visel A. Prabhakar S. Akiyama J.A. Shoukry M. Lewis K.D. Holt A. Plajzer-Frick I. Afzal V. Rubin E.M. Pennacchio L.A. Ultraconservation identifies a small subset of extremely constrained developmental enhancers.Nat. Genet. 2008; 40: 158-160Crossref PubMed Scopus (244) Google Scholar) in the genomic vicinity of 79 genes with a known role in forebrain development or function (Table S1B), and we identified 231 additional candidate forebrain enhancer sequences (Table S1C). Combined, these two data sets comprised a total of 4,656 noncoding sequence elements that we hypothesized to be enriched in forebrain enhancers. To validate candidate telencephalon enhancer sequences and define their in vivo activities in greater detail, we selected 329 elements predicted to be enhancers by conservation and/or ChIP-seq for experimental testing (Table S1D). Nearly all of these selected elements were located near genes with a known function in the forebrain (Table S1B). In order to focus on the most conserved core regulatory architecture of mammalian telencephalon development, only ChIP-seq peaks that were detectably conserved between the human and mouse genome were tested. Regardless of the identification method, all tested sequences showed evidence of significant evolutionary constraint (phastCons scores ranging from 415 to 931, median 798; Table S1D). The selected candidate enhancer sequences were amplified from human genomic DNA, cloned into an enhancer reporter vector (Hsp68-LacZ), and used to generate transgenic mice by pronuclear injection (see Experimental Procedures). Transgenic embryos were stained for reporter gene (LacZ) activity at e11.5, and reporter expression was annotated using established reproducibility criteria (Pennacchio et al., 2006Pennacchio L.A. Ahituv N. Moses A.M. Prabhakar S. Nobrega M.A. Shoukry M. Minovitsky S. Dubchak I. Holt A. Lewis K.D. et al.In vivo enhancer analysis of human conserved non-coding sequences.Nature. 2006; 444: 499-502Crossref PubMed Scopus (875) Google Scholar). Only elements that drove expression in the forebrain in at least three embryos, each of them corresponding to an independent transgenic integration event, were considered as reproducible forebrain enhancers. In total, 105 of the 329 (32%) candidate sequences tested were reproducible forebrain enhancers at e11.5, of which 36 showed reproducible expression exclusively in the forebrain (Table S1D). For comparison, in previous transgenic assays of p300-binding sites in two different nonneuronal tissues, limb buds and the heart, only 4 of the 155 (2.6%) tested sequences had reproducible forebrain enhancer activity at e11.5 (Blow et al., 2010Blow M.J. McCulley D.J. Li Z. Zhang T. Akiyama J.A. Holt A. Plajzer-Frick I. Shoukry M. Wright C. Chen F. et al.ChIP-Seq identification of weakly conserved heart enhancers.Nat. Genet. 2010; 42: 806-810Crossref PubMed Scopus (332) Google Scholar; Visel et al., 2009aVisel A. Blow M.J. Li Z. Zhang T. Akiyama J.A. Holt A. Plajzer-Frick I. Shoukry M. Wright C. Chen F. et al.ChIP-seq accurately predicts tissue-specific activity of enhancers.Nature. 2009; 457: 854-858Crossref PubMed Scopus (1252) Google Scholar). Enhancer candidate sequences that overlapped p300 ChIP-seq peaks were more enriched in verifiable in vivo forebrain enhancers than extremely conserved sequences that showed no evidence of p300 binding (58% compared to 23%, Table S1D). Selected examples of reproducible forebrain enhancers whose in vivo activity was confirmed in transgenic mice are shown in Figure 1, and whole-mount images for all validated enhancers are accessible online through the Vista Enhancer Browser (Visel et al., 2007Visel A. Minovitsky S. Dubchak I. Pennacchio L.A. VISTA Enhancer Browser—a database of tissue-specific human enhancers.Nucleic Acids Res. 2007; 35: D88-D92Crossref PubMed Scopus (683) Google Scholar). To define the precise spatial expression patterns of telencephalic enhancers active at e11.5, we performed high-resolution analysis on a set of 145 enhancers (Table S1E). These sequences were selected from the 105 forebrain enhancers discovered in the present study and from complementary sets of forebrain enhancers identified at whole-mount resolution in previous enhancer screens (Pennacchio et al., 2006Pennacchio L.A. Ahituv N. Moses A.M. Prabhakar S. Nobrega M.A. Shoukry M. Minovitsky S. Dubchak I. Holt A. Lewis K.D. et al.In vivo enhancer analysis of human conserved non-coding sequences.Nature. 2006; 444: 499-502Crossref PubMed Scopus (875) Google Scholar; Visel et al., 2008Visel A. Prabhakar S. Akiyama J.A. Shoukry M. Lewis K.D. Holt A. Plajzer-Frick I. Afzal V. Rubin E.M. Pennacchio L.A. Ultraconservation identifies a small subset of extremely constrained developmental enhancers.Nat. Genet. 2008; 40: 158-160Crossref PubMed Scopus (244) Google Scholar, Visel et al., 2009aVisel A. Blow M.J. Li Z. Zhang T. Akiyama J.A. Holt A. Plajzer-Frick I. Shoukry M. Wright C. Chen F. et al.ChIP-seq accurately predicts tissue-specific activity of enhancers.Nature. 2009; 457: 854-858Crossref PubMed Scopus (1252) Google Scholar). For each enhancer, a full set of contiguous coronal paraffin sections (average: 220 sections) was obtained. Full-resolution digital images of more than 32,000 sections are available through the Vista Enhancer Browser (Visel et al., 2007Visel A. Minovitsky S. Dubchak I. Pennacchio L.A. VISTA Enhancer Browser—a database of tissue-specific human enhancers.Nucleic Acids Res. 2007; 35: D88-D92Crossref PubMed Scopus (683) Google Scholar). Selected sections of patterns driven by different enhancers in subregions of the pallium (cortex), subpallium (basal ganglia), and eminentia thalami (telencephalic-diencephalic connection) are shown in Figures 2 and 3, illustrating the diversity of spatial specificities observed.Figure 3Subset of Forebrain Enhancers with Activity in Different Subregions of the Mouse Subpallium and Eminentia ThalamiShow full caption(A–E) Selected enhancers that target LacZ expression (A) predominantly or exclusively to subregions of the LGE, (B) predominantly to the MGE, (D) both to the LGE and to MGE, and (E) to the EMT. (C) Schematic overview of structures in the approximate sectioning plane shown in (A), (B), (D), and (E). Depending on the rostrocaudal extent of staining, for some enhancers, more rostral or caudal planes were chosen to illustrate salient features of the respective patterns.(F and G) Comparison of enhancer activities between e11.5, e13.5, and e15.5. White arrowheads indicate cell populations whose location is consistent with migration from the MGE, through the LGE, and to the cortex.CP, choroid plexus; Cx, cortex; CxP, cortical plate; EMT, eminentia thalami; DP, dorsal pallium; LGE, lateral ganglionic eminence; LP, lateral pallium; MGE, medial ganglionic eminence; MP, medial pallium; MZ, marginal zone; POA, preoptic area; Str, striatum; VP, ventral pallium; Th, thalamus. See also Figure S1 and Tables S1A–S1D.View Large Image Figure ViewerDownload Hi-res image Download (PPT) (A–E) Selected enhancers that target LacZ expression (A) predominantly or exclusively to subregions of the LGE, (B) predominantly to the MGE, (D) both to the LGE and to MGE, and (E) to the EMT. (C) Schematic overview of structures in the approximate sectioning plane shown in (A), (B), (D), and (E). Depending on the rostrocaudal extent of staining, for some enhancers, more rostral or caudal planes were chosen to illustrate salient features of the respective patterns. (F and G) Comparison of enhancer activities between e11.5, e13.5, and e15.5. White arrowheads indicate cell populations whose location is consistent with migration from the MGE, through the LGE, and to the cortex. CP, choroid plexus; Cx, cortex; CxP, cortical plate; EMT, eminentia thalami; DP, dorsal pallium; LGE, lateral ganglionic eminence; LP, lateral pallium; MGE, medial ganglionic eminence; MP, medial pallium; MZ, marginal zone; POA, preoptic area; Str, striatum; VP, ventral pallium; Th, thalamus. See also Figure S1 and Tables S1A–S1D. In addition to the spatial activity patterns of all 145 enhancers studied at e11.5, we also examined the temporal activities of a subset of these enhancers at later prenatal stages of telencephalon development (Figures 2S, 3F, and 3G). These temporal comparisons showed that the spatial patterns of enhancer activity were largely constant. In two cases, enhancers active in subregions of the subpallium at e11.5 displayed characteristic features of subpallial cell populations (interneurons) that tangentially migrate to the pallium. At e13.5, these cells had just arrived in the ventrolateral pallium (hs692 and hs799), and by e15.5 they were in the dorsal pallium (hs799, arrowheads in Figures 3F and 3G). These results support the notion that enhancers regulate both spatial and temporal aspects of telencephalic gene expression in patterns consistent with the biology of these regions and cell types. To facilitate analysis by computational methods, we devised a standardized neuroanatomical annotation scheme for the e11.5 stage of telencephalon development (Figures 2A, 3C, and S1 and Table S1E). All telencephalon enhancer activity patterns examined in this study were annotated using this standardized annotation scheme, in some cases complemented by descriptions that further subdivide the standardized domains or are restricted to subsets of cells (Table S1E). The standardized annotations assigned to enhancers enable computational analysis of their activity patterns as well as a comparison to expression patterns of their presumptive target genes at this stage of development. To test whether the telencephalon enhancers examined at high resolution generally recapitulate the spatial expression patterns of their presumptive target genes, we compared their LacZ reporter activities to RNA in situ hybridization data. For example, the Arx gene is expressed in both subpallial and pallial regions, with increasing expression in pallial regions from e11.5 to e13.5 (Figure 4A). We found that there are at least four distant-acting telencephalic enhancers in this extended locus, two of which drive subpallial and two of which drive pallial expression, indicating that developmental Arx regulation is more complex than initially suggested (Colasante et al., 2008Colasante G. Collombat P. Raimondi V. Bonanomi D. Ferrai C. Maira M. Yoshikawa K. Mansouri A. Valtorta F. Rubenstein J.L. Broccoli V. Arx is a direct target of Dlx2 and thereby contributes to the tangential migration of GABAergic interneurons.J. Neurosci. 2008; 28: 10674-10686Crossref PubMed Scopus (117) Google Scholar). In addition, comparison of other genes with well-established roles in telencephalon development (Lef1, Wnt8b, Gsx2, Nr2f1) to nearby enhancers also revealed examples of spatially concordant enhancer activity and RNA expression (Figures 4B–4E). A recurring feature of these comparisons is the restriction of individual enhancer activities to subregions of the respective gene expression patterns, supporting the modular structure of telencephalic enhancer architecture. For instance, hs687 activity in the lateral ganglionic eminence (LGE) matches Gsx2 RNA expression, whereas the latter is also expressed in the medial ganglionic eminence (MGE); hs1172 activity in the pallium matches Nr2f1 RNA expression, whereas the gene is also expressed in the subpallium. To assess whether these illustrative examples are representative of a general congruence between enhancer activity patterns and the expression of nearby genes, we performed a quantitative correlation analysis across the available data set (see Extended Experimental Procedures for details). Overall, we found a highly significant correlation between the activity patterns of enhancers and telencephalic expression patterns of nearby annotated genes (p = 0.0003, Mann-Whitney test, Figure 4F). In addition to the high-resolution comparisons of enhancer and gene activity patterns, we also examined whether the genome-wide set of 4,425 forebrain enhancer candidate sequences identified by ChIP-seq from embryonic mouse forebrain tissue is associated with genes with known functions in the telencephalon. Unbiased genome-wide assessment (McLean et al., 2010McLean C.Y. Bristor D. Hiller M. Clarke S.L. Schaar B.T. Lowe C.B. Wenger A.M. Bejerano G. GREAT improves functional interpretation of cis-regulatory regions.Nat. Biotechnol. 2010; 28: 495-501Crossref PubMed Scopus (2491) Google Scholar) showed highly significant enrichment in genes that cause forebrain-related phenotypes when deleted in mouse models (Table S2). These observations support on a genomic scale that the large set of forebrain candidate enhancers predicted by ChIP-seq in this study is enriched near genes that are involved in telencephalon development. A large set of telencephalon enhancers, analyzed at high spatial resolution and annotated to a standardized scheme, offers the possibility to examine sequence features that are associated with in vivo activity in different telencephalic subregions. To explore this regulatory code, we trained a random forest (RF) classifier (Breiman, 2001Breiman L. Random Forests.Mach. Learn. 2001; 45: 5-32Crossref Scopus (65007) Google Scholar; Bureau et al., 2005Bureau A. Dupuis J. Falls K. Lunetta K.L. Hayward B. Keith T.P. Van Eerdewegh P. Identifying SNPs predictive of phenotype using random forests.Genet. Epidemiol. 2005; 28: 171-182Crossref PubMed Scopus (267) Google Scholar; Cummings and Segal, 2004Cummings M.P. Segal M.R. Few amino acid positions in rpoB are associated with most of the rifampin resistance in Mycobacterium tuberculosis.BMC Bioinformatics. 2004; 5: 137Crossref PubMed Scopus (21) Google Scholar; Lunetta et al., 2004Lunetta K.L. Hayward L.B. Segal J. Van Eerdewegh P. Screening large-scale association study data: exploiting interactions using random forests.BMC Genet. 2004; 5: 32Crossref PubMed Scopus (339) Google Scholar) to discriminate between random genomic sequences and enhancers active in (1) pallium only, (2) pallium and subpallium (compound pattern), or (3) subpallium only (see Figures 5, Figure S2, Figure S3, Figure S4, Figure S5, and Extended Experimental Procedures). Classification is based on the presence or absence of combinations of sequence motifs matching known transcription factor binding sites (Bryne et al., 2008Bryne J.C. Valen E. Tang M.H. Marstrand T. Winther O. da Piedade I. Krogh A. Lenhard B. Sandelin A. JASPAR, the open access database of transcription factor-binding profiles: new content and tools in the 2008 update.Nucleic Acids Res. 2008; 36: D102-D106Crossref PubMed Scopus (546) Google Scholar; Matys et al., 2006Matys V. Kel-Margoulis O.V. Fricke E. Liebich I. Land S. Barre-Dirrie A. Reuter I. Chekmenev D. Krull M. Hornischer K. et al.TRANSFAC and its module TRANSCompel: transcriptional gene regulation in eukaryotes.Nucleic Acids Res. 2006; 34: D108-D110Crossref PubMed Scopus (1701) Google Scholar). The five most relevant motifs distinguishing the three classes of enhancers and their respective importance are shown in Figure 5B (for additional motifs, see Figure S2 and Table S1G). We did not observe any single motif that was sufficient to accurately discriminate between the different classes of enhancers, suggesting that only the combinatorial binding of multiple transcription factors determines the observed spatial regulatory activity. The majority of the most discriminatory motifs (at least 60% of the top 15 motifs characterizing enhancers active in each of the telencephalic subregions considered) correspond to predicted binding sites for homeodomain-containing transcription factors, consistent with the known critical role of these proteins in telencephalon development (Hébert and Fishell, 2008Hébert J.M. Fishell G. The genetics of early telencephalon patterning: some assembly required.Nat. Rev. Neurosci. 2008; 9: 678-685Crossref PubMed Scopus (270) Google Scholar). Figure S3 summarizes the enrichment of the 15 most relevant motifs for enhancer activity in the three different telencephalic subregions considered. Despite possible ambiguities associated with computational transcription factor binding site predictions, the RF classifier accurately predicts ∼80% of the sequences (see Extended Experimental Procedures and Table S3). Sequence motifs with high quantitative importance for discriminating between different classes of telencephalon enhancers are overall more conserved in evolution compared to nonimportant motifs, supporting their functional relevance (Figure S4).Figure S2Relative Importance of Transcription Factor Binding Sites, Related to Figure 5Show full captionMost relevant binding site occurrence for the prediction of three different classes of forebrain enhancers. Forebrain Enhancers (pallium, subpallium, and pallium and subpallium enhancers) ranked in decreasing order of importance with respect to the mean decrease in prediction accuracy. The panel on the bottom right shows the overall top ranking binding sites and their mean decrease in accuracy and GINI measure in discriminating forebrain enhancers and control genomic regions.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Figure S3Distribution of Most Important Transcription Factor Binding Sites, Related to Figure 5Show full captionDistribution of most important TF-binding sites. The heat map shows the over-/under-rep" @default.
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• W2060316084 title "A High-Resolution Enhancer Atlas of the Developing Telencephalon" @default.
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• W2060316084 doi "https://doi.org/10.1016/j.cell.2012.12.041" @default.
• W2060316084 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/3660042" @default.
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