Human Gene Regulation
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1 Human Gene Regulation 4
2 Transcriptional networks underlying development ~20,000 genes take up 2% of the human genome. 1,000,000 gene regulation regions (promoters, enhancers, silencers, insulators) controlling our genes take up >10%. 99% of gene regulation regions were never seen before the human genome was sequenced. We study these switches. B Gene H H Gene N Gene N B Gene
3 Why study gene regulation? Large, hitherto invisible, disease susceptibility layer Encodes causality in gene regulatory networks Key contributions to genome and phenotype evolution Great promise for human health
4 How to Understand Genomic Datasets? Genomic Regions Enrichment of Annotations Tool job submissions per day, from 7,000 IP addrs >100,000 jobs served, >100 citations
5 Extend From Analysis to Predictions SRF T cell Term ChIP-seq PRISM actin cytoskeleton structural constituent of muscle dilated heart ventricles regulation of insulin secretion Discovers novel functions for hundreds of transcription factors. Known functions supported by hundreds of novel binding sites.
6 interactions appear to be direct and which additional transcriptio work. cesses. Comparing We predict these in data our to preliminary Combine factors may Genetics participate in the with network. Genomics: We predict in our prelim E14.5 network that 4 of Predicted the 5 interactions genomic network. from Black: our genetic netw suggests direct genetic interaction From are direct, Description via novel enhancers. (see to background Understanding We figure), predict red: novel. the 5th genetic inter (Fezf2 repression of Tbr1) is mediated by Satb2. We also predic Tbr1 and Satb2 autoregulation. Lastly, we predict a role for additional interactions, including Tbr1 and Satb2 autoregulation corticothalamic temporally l neocortex and using spatially specific eractions from our genetic network t E14.5 and E16.5 by The genetic network of sets, e predict I will comprehensively the 5th genetic interaction projection neuron fate ill iated then by apply Satb2. the We also specification predict we will extend ites in FACS sorted using functional and d E18.5 by which Sox5 computational genomics. ulations provides a detailed view of all l neocortex Tbr1 measurements Fezf2 Satb2 helps separate e to broader cortical processes. + = t enhancer networks Ctip2 that control Bhlhe22 ic neocortex. genes and enhancers, we predict corticothalamic the enhancers with subcortical callosal d associate is Fig 3. The genetic network of ription projection factors, Classical neuron fate known specification interactions Functional and & T studied by the McConnell lab. Known cers s that Genetics mediate known & genetic + interin projection and preliminary neuron predicted interactions fate specification. direct genetic interactions in black Computational = m get. from our Development data in red. Genomics uron fate specification. nections between transcription factors, on enhancer assays test activity and sgenics test enhancer layer specificity. effect of critical projection neuron Tbr1 Sox5 3 Fezf2 Ctip2 Bhlhe22 subcortical Satb2 callosal Fig 3. The genetic network of projection Rapid neuron Discovery, fate specification studied by the McConnell lab. Known direct Design genetic interactions Principles black and preliminary predicted interactions from our data in red.
7 Gene regulation of tissue development: Measure, Predict, Discover Work with Sue McConnell
8 Analyze Personal Human Genomes Associate to nearest gene(s) Personal cis variant 1 Target gene Self reported medical summary Any relationship? 3 2 Is the group of affected target genes enriched for a particular function or phenotype?
9 Test human disease mutations Section 1 Enhancer / HuC Target gene Work with Philippe Mourrain
10 Identifying regulatory elements uniquely lost in human Work with David Kingsley 17
11 The first human enhancers conserved to protostomes Work with Nadav Ahituv
12 Correlate independent trait loss with gene/enhancer loss trait matching genomic loci [Hiller et al., 2012a,b]
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