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      Creating cell type-specific mutants by enhancer mutagenesis

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          Abstract

          In this Outlook, Crews discusses the usefulness of creating cell type-specific mutants by mutating enhancers that control different patterns of expression through CRISPR/Cas9, as shown in Rogers et al. in this issue.

          Abstract

          Cell signaling plays an essential role in development, and knowledge of the identities of the cells sending the signal is critical. This can be a challenge, since signaling pathways and ligands are commonly used at multiple times and in multiple cell types during development. One solution to this problem is to create cell type-specific mutants using CRISPR/Cas9 to mutate enhancers that control different patterns of expression. In this issue of Genes & Development, Rogers and colleagues (pp. 634–638) provide the first use of this method in Drosophila to solve a long-standing issue in patterning of the embryonic central nervous system.

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          Systematic localization of common disease-associated variation in regulatory DNA.

          Matthew Maurano, Richard Humbert, Eric Rynes … (2012)
          Genome-wide association studies have identified many noncoding variants associated with common diseases and traits. We show that these variants are concentrated in regulatory DNA marked by deoxyribonuclease I (DNase I) hypersensitive sites (DHSs). Eighty-eight percent of such DHSs are active during fetal development and are enriched in variants associated with gestational exposure-related phenotypes. We identified distant gene targets for hundreds of variant-containing DHSs that may explain phenotype associations. Disease-associated variants systematically perturb transcription factor recognition sequences, frequently alter allelic chromatin states, and form regulatory networks. We also demonstrated tissue-selective enrichment of more weakly disease-associated variants within DHSs and the de novo identification of pathogenic cell types for Crohn's disease, multiple sclerosis, and an electrocardiogram trait, without prior knowledge of physiological mechanisms. Our results suggest pervasive involvement of regulatory DNA variation in common human disease and provide pathogenic insights into diverse disorders.
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            REDfly v3.0: toward a comprehensive database of transcriptional regulatory elements in Drosophila

            Steven Gallo, Dave Gerrard, David Miner … (2010)
            The REDfly database of Drosophila transcriptional cis-regulatory elements provides the broadest and most comprehensive available resource for experimentally validated cis-regulatory modules and transcription factor binding sites among the metazoa. The third major release of the database extends the utility of REDfly as a powerful tool for both computational and experimental studies of transcription regulation. REDfly v3.0 includes the introduction of new data classes to expand the types of regulatory elements annotated in the database along with a roughly 40% increase in the number of records. A completely redesigned interface improves access for casual and power users alike; among other features it now automatically provides graphical views of the genome, displays images of reporter gene expression and implements improved capabilities for database searching and results filtering. REDfly is freely accessible at http://redfly.ccr.buffalo.edu.
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              Genome-scale functional characterization of Drosophila developmental enhancers in vivo.

              Evgeny Kvon, Tomas Kazmar, Gerald Stampfel … (2014)
              Transcriptional enhancers are crucial regulators of gene expression and animal development and the characterization of their genomic organization, spatiotemporal activities and sequence properties is a key goal in modern biology. Here we characterize the in vivo activity of 7,705 Drosophila melanogaster enhancer candidates covering 13.5% of the non-coding non-repetitive genome throughout embryogenesis. 3,557 (46%) candidates are active, suggesting a high density with 50,000 to 100,000 developmental enhancers genome-wide. The vast majority of enhancers display specific spatial patterns that are highly dynamic during development. Most appear to regulate their neighbouring genes, suggesting that the cis-regulatory genome is organized locally into domains, which are supported by chromosomal domains, insulator binding and genome evolution. However, 12 to 21 per cent of enhancers appear to skip non-expressed neighbours and regulate a more distal gene. Finally, we computationally identify cis-regulatory motifs that are predictive and required for enhancer activity, as we validate experimentally. This work provides global insights into the organization of an animal regulatory genome and the make-up of enhancer sequences and confirms and generalizes principles from previous studies. All enhancer patterns are annotated manually with a controlled vocabulary and all results are available through a web interface (http://enhancers.starklab.org), including the raw images of all microscopy slides for manual inspection at arbitrary zoom levels.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Genes Dev
                Journal ID (iso-abbrev): Genes Dev
                Journal ID (hwp): genesdev
                Journal ID (pmc): genesdev
                Journal ID (publisher-id): GAD
                Title: Genes & Development
                Publisher: Cold Spring Harbor Laboratory Press
                ISSN (Print): 0890-9369
                ISSN (Electronic): 1549-5477
                Publication date (Print): 1 April 2017
                Volume: 31
                Issue: 7
                Pages: 629-631
                Affiliations
                Department of Biochemistry and Biophysics, School of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA
                Author notes
                Corresponding author: steve_crews@ 123456unc.edu
                Article
                Medline ID: 8711660
                DOI: 10.1101/gad.299586.117
                PMC ID: 5411702
                PubMed ID: 28446593
                SO-VID: 1fb178d7-9e86-448a-bd20-94dc69a16542
                Copyright © © 2017 Crews; Published by Cold Spring Harbor Laboratory Press
                License:

                This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genesdev.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.

                History
                Page count
                Pages: 3
                Funding
                Funded by: National Institutes of Health http://dx.doi.org/10.13039/100000002
                Award ID: NS64264
                Categories
                Subject: 8
                Subject: 22
                Subject: Outlook

                Keywords: drosophila embryo,egfr regulatory networks,rhomboid,intermediate neuroblasts defective,central nervous system
                Data availability:
                Keywords: drosophila embryo, egfr regulatory networks, rhomboid, intermediate neuroblasts defective, central nervous system

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