Massively parallel decoding of mammalian regulatory sequences supports a flexible organizational model
Robin P. Smith,Leila Taher,Rupali P Patwardhan,Mee J. Kim,Fumitaka Inoue,Jay Shendure,Ivan Ovcharenko,Nadav Ahituv +7 more
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TLDR
It is found that certain transcription factors act as direct drivers of gene expression in homotypic clusters of binding sites, independent of spacing between sites, whereas others function only synergistically, providing quantitative support for a flexible model of regulatory element activity.Abstract:
Despite continual progress in the cataloging of vertebrate regulatory elements, little is known about their organization and regulatory architecture. Here we describe a massively parallel experiment to systematically test the impact of copy number, spacing, combination and order of transcription factor binding sites on gene expression. A complex library of ∼5,000 synthetic regulatory elements containing patterns from 12 liver-specific transcription factor binding sites was assayed in mice and in HepG2 cells. We find that certain transcription factors act as direct drivers of gene expression in homotypic clusters of binding sites, independent of spacing between sites, whereas others function only synergistically. Heterotypic enhancers are stronger than their homotypic analogs and favor specific transcription factor binding site combinations, mimicking putative native enhancers. Exhaustive testing of binding site permutations suggests that there is flexibility in binding site order. Our findings provide quantitative support for a flexible model of regulatory element activity and suggest a framework for the design of synthetic tissue-specific enhancers.read more
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Transcriptional enhancers: from properties to genome-wide predictions.
TL;DR: How properties of enhancer sequences and chromatin are used to predict enhancers in genome-wide studies are discussed and recently developed high-throughput methods that allow the direct testing and identification of enhancers on the basis of their activity are covered.
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Large-scale de novo DNA synthesis: technologies and applications
Sriram Kosuri,George M. Church +1 more
TL;DR: Methods and caveats for the de novo synthesis of DNA are summarized, with particular emphasis on recent technologies that allow for large-scale and low-cost production.
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Ever-Changing Landscapes: Transcriptional Enhancers in Development and Evolution.
TL;DR: An overview of emerging principles of enhancers function, current models of enhancer architecture, genomic substrates from which enhancers emerge during evolution, and the influence of three-dimensional genome organization on long-range gene regulation are given.
Journal ArticleDOI
ChIP-Atlas: a data-mining suite powered by full integration of public ChIP-seq data
Shinya Oki,Tazro Ohta,Go Shioi,Hideki Hatanaka,Osamu Ogasawara,Yoshihiro Okuda,Hideya Kawaji,Ryo Nakaki,Jun Sese,Chikara Meno +9 more
TL;DR: ChIP‐Atlas is superior to other platforms in terms of data number and functionality for data mining across thousands of ChIP‐seq experiments, and it provides insight into gene regulatory networks and epigenetic mechanisms.
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Absence of a simple code: how transcription factors read the genome
TL;DR: Structural views have been complemented with data from high-throughput in vitro and in vivo explorations of the DNA-binding preferences of many TFs to expand the understanding of TF-DNA interactions.
References
More filters
Journal ArticleDOI
Controlling the false discovery rate: a practical and powerful approach to multiple testing
Yoav Benjamini,Yosef Hochberg +1 more
TL;DR: In this paper, a different approach to problems of multiple significance testing is presented, which calls for controlling the expected proportion of falsely rejected hypotheses -the false discovery rate, which is equivalent to the FWER when all hypotheses are true but is smaller otherwise.
Journal ArticleDOI
Fast and accurate short read alignment with Burrows–Wheeler transform
Heng Li,Richard Durbin +1 more
TL;DR: Burrows-Wheeler Alignment tool (BWA) is implemented, a new read alignment package that is based on backward search with Burrows–Wheeler Transform (BWT), to efficiently align short sequencing reads against a large reference sequence such as the human genome, allowing mismatches and gaps.
Journal ArticleDOI
Genome-Wide Mapping of in Vivo Protein-DNA Interactions
David S. Johnson,Ali Mortazavi,Ali Mortazavi,Richard M. Myers,Richard M. Myers,Barbara J. Wold,Barbara J. Wold +6 more
TL;DR: A large-scale chromatin immunoprecipitation assay based on direct ultrahigh-throughput DNA sequencing was developed, which was then used to map in vivo binding of the neuron-restrictive silencer factor (NRSF; also known as REST) to 1946 locations in the human genome.
Journal ArticleDOI
Detection of influential observation in linear regression
TL;DR: In this article, a measure based on confidence ellipsoids is developed for judging the contribution of each data point to the determination of the least squares estimate of the parameter vector in full rank linear regression models.
Journal ArticleDOI
TRANSFAC® and its module TRANSCompel®: transcriptional gene regulation in eukaryotes
V. Matys,Olga V. Kel-Margoulis,Ellen Fricke,Ines Liebich,Sigrid Land,A. Barre-Dirrie,Ingmar Reuter,D. Chekmenev,Mathias Krull,Klaus Hornischer,Nico Voss,Philip Stegmaier,Birgit Lewicki-Potapov,H. Saxel,Alexander E. Kel,Edgar Wingender +15 more
TL;DR: The TRANSFAC® database on transcription factors, their binding sites, nucleotide distribution matrices and regulated genes as well as the complementing database TRANSCompel® on composite elements have been further enhanced on various levels.
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