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Gene Regulation

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59 papers 25 to 100 followers
By Hemangi Chaudhari Graduate student
Gabriel E Zentner, Sivakanthan Kasinathan, Beibei Xin, Remo Rohs, Steven Henikoff
Chromatin endogenous cleavage (ChEC) uses fusion of a protein of interest to micrococcal nuclease (MNase) to target calcium-dependent cleavage to specific genomic loci in vivo. Here we report the combination of ChEC with high-throughput sequencing (ChEC-seq) to map budding yeast transcription factor (TF) binding. Temporal analysis of ChEC-seq data reveals two classes of sites for TFs, one displaying rapid cleavage at sites with robust consensus motifs and the second showing slow cleavage at largely unique sites with low-scoring motifs...
October 22, 2015: Nature Communications
Walid A Al-Zyoud, Robert M G Hynson, Lorraine A Ganuelas, Adelle C F Coster, Anthony P Duff, Matthew A B Baker, Alastair G Stewart, Eleni Giannoulatou, Joshua W K Ho, Katharina Gaus, Dali Liu, Lawrence K Lee, Till Böcking
Mechanisms for transcription factor recognition of specific DNA base sequences are well characterized and recent studies demonstrate that the shape of these cognate binding sites is also important. Here, we uncover a new mechanism where the transcription factor GabR simultaneously recognizes two cognate binding sites and the shape of a 29 bp DNA sequence that bridges these sites. Small-angle X-ray scattering and multi-angle laser light scattering are consistent with a model where the DNA undergoes a conformational change to bend around GabR during binding...
February 18, 2016: Nucleic Acids Research
Chuanying Chen, B Montgomery Pettitt
The binding process of a protein with a DNA involves three stages: approach, encounter, and association. It has been known that the complexation of protein and DNA involves mutual conformational changes, especially for a specific sequence association. However, it is still unclear how the conformation and the information in the DNA sequences affects the binding process. What is the extent to which the DNA structure adopted in the complex is induced by protein binding, or is instead intrinsic to the DNA sequence? In this study, we used the multiscale simulation method to explore the binding process of a protein with DNA in terms of DNA sequence, conformation, and interactions...
February 2, 2016: Biophysical Journal
Yair Glick, Yaron Orenstein, Dana Chen, Dorit Avrahami, Tsaffrir Zor, Ron Shamir, Doron Gerber
Protein binding to DNA is a fundamental process in gene regulation. Methodologies such as ChIP-Seq and mapping of DNase I hypersensitive sites provide global information on this regulation in vivo In vitro methodologies provide valuable complementary information on protein-DNA specificities. However, current methods still do not measure absolute binding affinities. There is a real need for large-scale quantitative protein-DNA affinity measurements. We developed QPID, a microfluidic application for measuring protein-DNA affinities...
April 7, 2016: Nucleic Acids Research
Simon M Carr, A Poppy Roworth, Cheryl Chan, Nicholas B La Thangue
Methylation of lysine and arginine residues on histones has long been known to determine both chromatin structure and gene expression. In recent years, the methylation of non-histone proteins has emerged as a prevalent modification which impacts on diverse processes such as cell cycle control, DNA repair, senescence, differentiation, apoptosis and tumourigenesis. Many of these non-histone targets represent transcription factors, cell signalling molecules and tumour suppressor proteins. Evidence now suggests that the dysregulation of methyltransferases, demethylases and reader proteins is involved in the development of many diseases, including cancer, and several of these proteins represent potential therapeutic targets for small molecule compounds, fuelling a recent surge in chemical inhibitor design...
December 2015: FEBS Journal
Cheryl A Scacheri, Peter C Scacheri
PURPOSE OF REVIEW: Clinical diagnostic sequencing currently focuses on identifying causal mutations in the exome, wherein most disease-causing mutations are known to occur. The rest of the genome is mostly comprised of regulatory elements that control gene expression, but these have remained largely unexplored in clinical diagnostics due to the high cost of whole genome sequencing and interpretive challenges. The purpose of this review is to illustrate examples of diseases caused by mutations in regulatory elements and introduce the diagnostic potential for whole genome sequencing...
December 2015: Current Opinion in Pediatrics
José M Santos-Pereira, Andrés Aguilera
R loops are nucleic acid structures composed of an RNA-DNA hybrid and a displaced single-stranded DNA. Recently, evidence has emerged that R loops occur more often in the genome and have greater physiological relevance, including roles in transcription and chromatin structure, than was previously predicted. Importantly, however, R loops are also a major threat to genome stability. For this reason, several DNA and RNA metabolism factors prevent R-loop formation in cells. Dysfunction of these factors causes R-loop accumulation, which leads to replication stress, genome instability, chromatin alterations or gene silencing, phenomena that are frequently associated with cancer and a number of genetic diseases...
October 2015: Nature Reviews. Genetics
Tae-Kyung Kim, Ramin Shiekhattar
With the explosion of genome-wide studies of regulated transcription, it has become clear that traditional definitions of enhancers and promoters need to be revisited. These control elements can now be characterized in terms of their local and regional architecture, their regulatory components, including histone modifications and associated binding factors, and their functional contribution to transcription. This Review discusses unifying themes between promoters and enhancers in transcriptional regulatory mechanisms...
August 27, 2015: Cell
Zing Tsung-Yeh Tsai, Shin-Han Shiu, Huai-Kuang Tsai
Transcription factor (TF) binding is determined by the presence of specific sequence motifs (SM) and chromatin accessibility, where the latter is influenced by both chromatin state (CS) and DNA structure (DS) properties. Although SM, CS, and DS have been used to predict TF binding sites, a predictive model that jointly considers CS and DS has not been developed to predict either TF-specific binding or general binding properties of TFs. Using budding yeast as model, we found that machine learning classifiers trained with either CS or DS features alone perform better in predicting TF-specific binding compared to SM-based classifiers...
August 2015: PLoS Computational Biology
Sara L Prescott, Rajini Srinivasan, Maria Carolina Marchetto, Irina Grishina, Iñigo Narvaiza, Licia Selleri, Fred H Gage, Tomek Swigut, Joanna Wysocka
cis-regulatory changes play a central role in morphological divergence, yet the regulatory principles underlying emergence of human traits remain poorly understood. Here, we use epigenomic profiling from human and chimpanzee cranial neural crest cells to systematically and quantitatively annotate divergence of craniofacial cis-regulatory landscapes. Epigenomic divergence is often attributable to genetic variation within TF motifs at orthologous enhancers, with a novel motif being most predictive of activity biases...
September 24, 2015: Cell
Johannes Schwerk, Ram Savan
Gene expression programs undergo constant regulation to quickly adjust to environmental stimuli that alter the physiological status of the cell, like cellular stress or infection. Gene expression is tightly regulated by multilayered regulatory elements acting in both cis and trans. Posttranscriptional regulation of the 3' untranslated region (UTR) is a powerful regulatory process that determines the rate of protein translation from mRNA. Regulatory elements targeting the 3' UTR include microRNAs, RNA-binding proteins, and long noncoding RNAs, which dramatically alter the immune response...
October 1, 2015: Journal of Immunology: Official Journal of the American Association of Immunologists
Gaurav K Varshney, Wuhong Pei, Matthew C LaFave, Jennifer Idol, Lisha Xu, Viviana Gallardo, Blake Carrington, Kevin Bishop, MaryPat Jones, Mingyu Li, Ursula Harper, Sunny C Huang, Anupam Prakash, Wenbiao Chen, Raman Sood, Johan Ledin, Shawn M Burgess
The use of CRISPR/Cas9 as a genome-editing tool in various model organisms has radically changed targeted mutagenesis. Here, we present a high-throughput targeted mutagenesis pipeline using CRISPR/Cas9 technology in zebrafish that will make possible both saturation mutagenesis of the genome and large-scale phenotyping efforts. We describe a cloning-free single-guide RNA (sgRNA) synthesis, coupled with streamlined mutant identification methods utilizing fluorescent PCR and multiplexed, high-throughput sequencing...
July 2015: Genome Research
Christopher M Vockley, Cong Guo, William H Majoros, Michael Nodzenski, Denise M Scholtens, M Geoffrey Hayes, William L Lowe, Timothy E Reddy
We report a novel high-throughput method to empirically quantify individual-specific regulatory element activity at the population scale. The approach combines targeted DNA capture with a high-throughput reporter gene expression assay. As demonstration, we measured the activity of more than 100 putative regulatory elements from 95 individuals in a single experiment. In agreement with previous reports, we found that most genetic variants have weak effects on distal regulatory element activity. Because haplotypes are typically maintained within but not between assayed regulatory elements, the approach can be used to identify causal regulatory haplotypes that likely contribute to human phenotypes...
August 2015: Genome Research
Peter Hansen, Jochen Hecht, Daniel M Ibrahim, Alexander Krannich, Matthias Truss, Peter N Robinson
Chromatin immunoprecipitation coupled with next-generation sequencing (ChIP-seq) is a powerful technology to identify the genome-wide locations of transcription factors and other DNA binding proteins. Computational ChIP-seq peak calling infers the location of protein-DNA interactions based on various measures of enrichment of sequence reads. In this work, we introduce an algorithm, Q, that uses an assessment of the quadratic enrichment of reads to center candidate peaks followed by statistical analysis of saturation of candidate peaks by 5' ends of reads...
September 2015: Genome Research
Can Cenik, Elif Sarinay Cenik, Gun W Byeon, Fabian Grubert, Sophie I Candille, Damek Spacek, Bilal Alsallakh, Hagen Tilgner, Carlos L Araya, Hua Tang, Emiliano Ricci, Michael P Snyder
Elucidating the consequences of genetic differences between humans is essential for understanding phenotypic diversity and personalized medicine. Although variation in RNA levels, transcription factor binding, and chromatin have been explored, little is known about global variation in translation and its genetic determinants. We used ribosome profiling, RNA sequencing, and mass spectrometry to perform an integrated analysis in lymphoblastoid cell lines from a diverse group of individuals. We find significant differences in RNA, translation, and protein levels suggesting diverse mechanisms of personalized gene expression control...
November 2015: Genome Research
Leslie Y Beh, Manuel M Müller, Tom W Muir, Noam Kaplan, Laura F Landweber
A conserved hallmark of eukaryotic chromatin architecture is the distinctive array of well-positioned nucleosomes downstream from transcription start sites (TSS). Recent studies indicate that trans-acting factors establish this stereotypical array. Here, we present the first genome-wide in vitro and in vivo nucleosome maps for the ciliate Tetrahymena thermophila. In contrast with previous studies in yeast, we find that the stereotypical nucleosome array is preserved in the in vitro reconstituted map, which is governed only by the DNA sequence preferences of nucleosomes...
November 2015: Genome Research
Daniel Savic, E Christopher Partridge, Kimberly M Newberry, Sophia B Smith, Sarah K Meadows, Brian S Roberts, Mark Mackiewicz, Eric M Mendenhall, Richard M Myers
Chromatin immunoprecipitation followed by next-generation DNA sequencing (ChIP-seq) is a widely used technique for identifying transcription factor (TF) binding events throughout an entire genome. However, ChIP-seq is limited by the availability of suitable ChIP-seq grade antibodies, and the vast majority of commercially available antibodies fail to generate usable data sets. To ameliorate these technical obstacles, we present a robust methodological approach for performing ChIP-seq through epitope tagging of endogenous TFs...
October 2015: Genome Research
Leeat Keren, David van Dijk, Shira Weingarten-Gabbay, Dan Davidi, Ghil Jona, Adina Weinberger, Ron Milo, Eran Segal
Genetically identical cells exposed to the same environment display variability in gene expression (noise), with important consequences for the fidelity of cellular regulation and biological function. Although population average gene expression is tightly coupled to growth rate, the effects of changes in environmental conditions on expression variability are not known. Here, we measure the single-cell expression distributions of approximately 900 Saccharomyces cerevisiae promoters across four environmental conditions using flow cytometry, and find that gene expression noise is tightly coupled to the environment and is generally higher at lower growth rates...
December 2015: Genome Research
Jichen Yang, Stephen A Ramsey
MOTIVATION: The position-weight matrix (PWM) is a useful representation of a transcription factor binding site (TFBS) sequence pattern because the PWM can be estimated from a small number of representative TFBS sequences. However, because the PWM probability model assumes independence between individual nucleotide positions, the PWMs for some TFs poorly discriminate binding sites from non-binding-sites that have similar sequence content. Since the local three-dimensional DNA structure ('shape') is a determinant of TF binding specificity and since DNA shape has a significant sequence-dependence, we combined DNA shape-derived features into a TF-generalized regulatory score and tested whether the score could improve PWM-based discrimination of TFBS from non-binding-sites...
November 1, 2015: Bioinformatics
Iris Dror, Tamar Golan, Carmit Levy, Remo Rohs, Yael Mandel-Gutfreund
Transcriptional regulation requires the binding of transcription factors (TFs) to short sequence-specific DNA motifs, usually located at the gene regulatory regions. Interestingly, based on a vast amount of data accumulated from genomic assays, it has been shown that only a small fraction of all potential binding sites containing the consensus motif of a given TF actually bind the protein. Recent in vitro binding assays, which exclude the effects of the cellular environment, also demonstrate selective TF binding...
September 2015: Genome Research
2015-07-24 18:43:02
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