Systematic mapping of functional enhancer-promoter connections with CRISPR interference

Gene expression in mammals is regulated by noncoding elements that can affect physiology and disease, yet the functions and target genes of most noncoding elements remain unknown. We present a high-throughput approach that uses clustered regularly interspaced short palindromic repeats (CRISPR) inter...

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Published in:	Science (American Association for the Advancement of Science) Vol. 354; no. 6313; pp. 769 - 773
Main Authors:	Fulco, Charles P, Munschauer, Mathias, Anyoha, Rockwell, Munson, Glen, Grossman, Sharon R, Perez, Elizabeth M, Kane, Michael, Cleary, Brian, Lander, Eric S, Engreitz, Jesse M
Format:	Journal Article
Language:	English
Published:	United States 11.11.2016
Subjects:	Cell Proliferation - genetics Chromosome Mapping - methods Clustered Regularly Interspaced Short Palindromic Repeats CRISPR-Cas Systems Disease - genetics Enhancer Elements, Genetic - genetics Enhancer Elements, Genetic - physiology GATA1 Transcription Factor - genetics Gene Expression Regulation High-Throughput Nucleotide Sequencing - methods Humans K562 Cells Promoter Regions, Genetic - genetics Promoter Regions, Genetic - physiology Proto-Oncogene Proteins c-myc - genetics Real-Time Polymerase Chain Reaction
ISSN:	1095-9203
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Abstract	Gene expression in mammals is regulated by noncoding elements that can affect physiology and disease, yet the functions and target genes of most noncoding elements remain unknown. We present a high-throughput approach that uses clustered regularly interspaced short palindromic repeats (CRISPR) interference (CRISPRi) to discover regulatory elements and identify their target genes. We assess >1 megabase of sequence in the vicinity of two essential transcription factors, MYC and GATA1, and identify nine distal enhancers that control gene expression and cellular proliferation. Quantitative features of chromatin state and chromosome conformation distinguish the seven enhancers that regulate MYC from other elements that do not, suggesting a strategy for predicting enhancer-promoter connectivity. This CRISPRi-based approach can be applied to dissect transcriptional networks and interpret the contributions of noncoding genetic variation to human disease.
AbstractList	Gene expression in mammals is regulated by noncoding elements that can affect physiology and disease, yet the functions and target genes of most noncoding elements remain unknown. We present a high-throughput approach that uses clustered regularly interspaced short palindromic repeats (CRISPR) interference (CRISPRi) to discover regulatory elements and identify their target genes. We assess >1 megabase of sequence in the vicinity of two essential transcription factors, MYC and GATA1, and identify nine distal enhancers that control gene expression and cellular proliferation. Quantitative features of chromatin state and chromosome conformation distinguish the seven enhancers that regulate MYC from other elements that do not, suggesting a strategy for predicting enhancer-promoter connectivity. This CRISPRi-based approach can be applied to dissect transcriptional networks and interpret the contributions of noncoding genetic variation to human disease.
Author	Grossman, Sharon R Cleary, Brian Fulco, Charles P Munson, Glen Munschauer, Mathias Anyoha, Rockwell Lander, Eric S Kane, Michael Perez, Elizabeth M Engreitz, Jesse M
Author_xml	– sequence: 1 givenname: Charles P surname: Fulco fullname: Fulco, Charles P organization: Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA – sequence: 2 givenname: Mathias surname: Munschauer fullname: Munschauer, Mathias organization: Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA – sequence: 3 givenname: Rockwell surname: Anyoha fullname: Anyoha, Rockwell organization: Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA – sequence: 4 givenname: Glen surname: Munson fullname: Munson, Glen organization: Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA – sequence: 5 givenname: Sharon R surname: Grossman fullname: Grossman, Sharon R organization: Department of Biology, MIT, Cambridge, MA 02139, USA – sequence: 6 givenname: Elizabeth M surname: Perez fullname: Perez, Elizabeth M organization: Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA – sequence: 7 givenname: Michael surname: Kane fullname: Kane, Michael organization: Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA – sequence: 8 givenname: Brian surname: Cleary fullname: Cleary, Brian organization: Computational and Systems Biology Program, MIT, Cambridge, MA 02139, USA – sequence: 9 givenname: Eric S surname: Lander fullname: Lander, Eric S email: engreitz@broadinstitute.org, lander@broadinstitute.org organization: Department of Biology, MIT, Cambridge, MA 02139, USA – sequence: 10 givenname: Jesse M surname: Engreitz fullname: Engreitz, Jesse M email: engreitz@broadinstitute.org, lander@broadinstitute.org organization: Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. engreitz@broadinstitute.org lander@broadinstitute.org
BackLink	https://www.ncbi.nlm.nih.gov/pubmed/27708057$$D View this record in MEDLINE/PubMed
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Copyright	Copyright © 2016, American Association for the Advancement of Science.
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Snippet	Gene expression in mammals is regulated by noncoding elements that can affect physiology and disease, yet the functions and target genes of most noncoding...
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SubjectTerms	Cell Proliferation - genetics Chromosome Mapping - methods Clustered Regularly Interspaced Short Palindromic Repeats CRISPR-Cas Systems Disease - genetics Enhancer Elements, Genetic - genetics Enhancer Elements, Genetic - physiology GATA1 Transcription Factor - genetics Gene Expression Regulation High-Throughput Nucleotide Sequencing - methods Humans K562 Cells Promoter Regions, Genetic - genetics Promoter Regions, Genetic - physiology Proto-Oncogene Proteins c-myc - genetics Real-Time Polymerase Chain Reaction
Title	Systematic mapping of functional enhancer-promoter connections with CRISPR interference
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