scholarly journals CCAT: Combinatorial Code Analysis Tool for transcriptional regulation

2013 ◽  
Vol 42 (5) ◽  
pp. 2833-2847 ◽  
Author(s):  
Peng Jiang ◽  
Mona Singh
Keyword(s):  
Embryo Development ◽  
Binding Sites ◽  
Developmental Stages ◽  
Chromatin Accessibility ◽  
Analysis Tool ◽  
Computational Framework ◽  
Code Analysis ◽  
Genome Wide ◽  
Transcriptional Regulatory ◽  
Combinatorial Code

Abstract Combinatorial interplay among transcription factors (TFs) is an important mechanism by which transcriptional regulatory specificity is achieved. However, despite the increasing number of TFs for which either binding specificities or genome-wide occupancy data are known, knowledge about cooperativity between TFs remains limited. To address this, we developed a computational framework for predicting genome-wide co-binding between TFs (CCAT, Combinatorial Code Analysis Tool), and applied it to Drosophila melanogaster to uncover cooperativity among TFs during embryo development. Using publicly available TF binding specificity data and DNaseI chromatin accessibility data, we first predicted genome-wide binding sites for 324 TFs across five stages of D. melanogaster embryo development. We then applied CCAT in each of these developmental stages, and identified from 19 to 58 pairs of TFs in each stage whose predicted binding sites are significantly co-localized. We found that nearby binding sites for pairs of TFs predicted to cooperate were enriched in regions bound in relevant ChIP experiments, and were more evolutionarily conserved than other pairs. Further, we found that TFs tend to be co-localized with other TFs in a dynamic manner across developmental stages. All generated data as well as source code for our front-to-end pipeline are available at http://cat.princeton.edu.

scholarly journals Prediction of genome-wide effects of single nucleotide variants on transcription factor binding

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Sebastian Carrasco Pro ◽  
Katia Bulekova ◽  
Brian Gregor ◽  
Adam Labadorf ◽  
Juan Ignacio Fuxman Bass
Keyword(s):  
Binding Sites ◽  
Cancer Type ◽  
Single Nucleotide Variants ◽  
Single Nucleotide ◽  
Regulatory Regions ◽  
Genome Wide ◽  
Transcriptional Regulatory ◽  
Gene Regulatory ◽  
The Impact ◽  
The Relationship

Abstract Single nucleotide variants (SNVs) located in transcriptional regulatory regions can result in gene expression changes that lead to adaptive or detrimental phenotypic outcomes. Here, we predict gain or loss of binding sites for 741 transcription factors (TFs) across the human genome. We calculated ‘gainability’ and ‘disruptability’ scores for each TF that represent the likelihood of binding sites being created or disrupted, respectively. We found that functional cis-eQTL SNVs are more likely to alter TF binding sites than rare SNVs in the human population. In addition, we show that cancer somatic mutations have different effects on TF binding sites from different TF families on a cancer-type basis. Finally, we discuss the relationship between these results and cancer mutational signatures. Altogether, we provide a blueprint to study the impact of SNVs derived from genetic variation or disease association on TF binding to gene regulatory regions.

scholarly journals Genome-wide effects of chromatin on vitamin D signaling

2020 ◽  
Vol 64 (4) ◽  
pp. R45-R56 ◽  
Author(s):  
Andrea Hanel ◽  
Henna-Riikka Malmberg ◽  
Carsten Carlberg
Keyword(s):  
Vitamin D ◽  
Binding Sites ◽  
Target Genes ◽  
Chromatin Accessibility ◽  
Transcription Start Sites ◽  
Dihydroxyvitamin D ◽  
Genome Wide ◽  
Spatio Temporal ◽  
Vitamin D Signaling ◽  
The Impact

Molecular endocrinology of vitamin D is based on the activation of the transcription factor vitamin D receptor (VDR) by the vitamin D metabolite 1α,25-dihydroxyvitamin D3. This nuclear vitamin D-sensing process causes epigenome-wide effects, such as changes in chromatin accessibility as well as in the contact of VDR and its supporting pioneer factors with thousands of genomic binding sites, referred to as vitamin D response elements. VDR binding enhancer regions loop to transcription start sites of hundreds of vitamin D target genes resulting in changes of their expression. Thus, vitamin D signaling is based on epigenome- and transcriptome-wide shifts in VDR-expressing tissues. Monocytes are the most responsive cell type of the immune system and serve as a paradigm for uncovering the chromatin model of vitamin D signaling. In this review, an alternative approach for selecting vitamin D target genes is presented, which are most relevant for understanding the impact of vitamin D endocrinology on innate immunity. Different scenarios of the regulation of primary upregulated vitamin D target genes are presented, in which vitamin D-driven super-enhancers comprise a cluster of persistent (constant) and/or inducible (transient) VDR-binding sites. In conclusion, the spatio-temporal VDR binding in the context of chromatin is most critical for the regulation of vitamin D target genes.

scholarly journals Rice LEAFY COTYLEDON1 hinders photosynthesis in the embryo development to promote seed dormancy

2021 ◽  
Author(s):  
Fu Guo ◽  
Peijing Zhang ◽  
Yan Wu ◽  
Guiwei Lian ◽  
Wu Liu ◽  
...  
Keyword(s):  
Seed Development ◽  
Embryo Development ◽  
Seed Dormancy ◽  
Binding Sites ◽  
Gene Network ◽  
Seed Maturation ◽  
Rice Seed ◽  
Genome Wide ◽  
Leafy Cotyledon1 ◽  
Ga Biosynthesis

LEAFY COTYLEDON1 (LEC1) is the central regulator of seed development. During seed development, rice embryo photosynthesis is completely blocked, which is different from Arabidopsis green embryo. However, effects of LEC1 on photosynthesis in developing seeds is largely elusive. We generated OsLEC1 mutants using the CRISPR/Cas9 technique. Oslec1 mutant seeds lost the ability of dormancy and triggered photosynthesis in embryos at the early developing stage. Transcriptome analysis demonstrated that Oslec1 mutation promoted photosynthesis and altered diverse hormonal pathways and stress response contributing to seed dormancy. Further, genome-wide identification of OsLEC1 binding sites demonstrated that OsLEC1 directly bound to genes involved in photosynthesis, photomorphogenesis, as well as abscisic acid (ABA) and gibberellin (GA) pathways, in seed maturation. We illustrated an OsLEC1-controlling gene network during seed development, including the interconnection between photosynthesis and ABA/GA biosynthesis/signalling. Our findings suggested that OsLEC1 is an inhibitor of photosynthesis during embryo development to promote rice seed maturation. This study would provide new understanding for the OsLEC1 regulatory mechanisms on photosynthesis in the monocot seed development.

scholarly journals Decoding functional regulatory maps via genomic evolutionary footprints in 63 green plants

2018 ◽  
Author(s):  
Feng Tian ◽  
De-Chang Yang ◽  
Yu-Qi Meng ◽  
Jinpu Jin ◽  
Ge Gao
Keyword(s):  
Binding Sites ◽  
Regulatory System ◽  
Regulatory Elements ◽  
Binding Affinities ◽  
Green Plants ◽  
Regulatory Interactions ◽  
Regulatory Systems ◽  
Genome Wide ◽  
Transcriptional Regulatory ◽  
Systematic Identification

AbstractSystematic identification of functional transcriptional regulatory interactions is essential for understanding regulatory systems. Here, we firstly established genome-wide conservation landscapes for 63 green plants of seven lineages and then developed an algorithm FunTFBS to screen for functional regulatory elements and interactions by coupling base-varied binding affinities of transcription factors with the evolutionary footprints on their binding sites. Using the FunTFBS and the conservation landscapes, we further identified over two million functional interactions for 21,346 TFs, charting functional regulatory maps of these 63 plants. Our work provides plant community with valuable resources to decode plant transcriptional regulatory system and genome sequences.

scholarly journals Morc3 silences endogenous retroviruses by enabling Daxx-mediated H3.3 incorporation

2020 ◽  
Author(s):  
Sophia Groh ◽  
Anna Viktoria Milton ◽  
Lisa Marinelli ◽  
Cara V. Sickinger ◽  
Heike Bollig ◽  
...  
Keyword(s):  
Binding Sites ◽  
Atp Hydrolysis ◽  
Chromatin Accessibility ◽  
Endogenous Retroviruses ◽  
Chromatin Modifications ◽  
Interaction Domain ◽  
Knock Out ◽  
Genome Wide ◽  
A Genome ◽  
Mammalian Genomes

ABSTRACTEndogenous retroviruses (ERVs) comprise a significant portion of mammalian genomes. Although, specific ERV loci feature regulatory roles for host gene expression, most ERV integrations are transcriptionally repressed by Setdb1 mediated H3K9me3 and DNA methylation. However, the protein network which regulates deposition of these chromatin modifications is still incompletely understood. Here, we performed a genome-wide sgRNA screen for genes involved in ERV silencing and identified the GHKL ATPase protein Morc3 as top scoring hit. Morc3 knock-out cells display de-repression, reduced H3K9me3 and increased chromatin accessibility of distinct ERV classes. We found that the GHKL ATPase domain of Morc3 is critical for ERV silencing, since mutants which cannot bind ATP, or which are defective in ATP hydrolysis cannot rescue the Morc3 ko phenotype. Proteomic analysis revealed that Morc3 mutant protein which cannot bind ATP fails to interact with the H3.3 chaperone Daxx. This interaction depends on Morc3 SUMOylation, as Daxx lacking the SUMO interaction domain shows reduced association with Morc3. Notably, in Morc3 ko cells, we observed strongly reduced H3.3 on Morc3 binding sites. Thus, our data demonstrate Morc3 as critical regulator of Daxx-mediated H3.3 incorporation to ERV regions.

scholarly journals B1 SINE-binding ZFP266 impedes reprogramming through suppression of chromatin opening by pioneering factors

2022 ◽  
Author(s):  
Daniel F Kaemena ◽  
Masahito Yoshihara ◽  
James Ashmore ◽  
Meryam Beniazza ◽  
Suling Zhao ◽  
...  
Keyword(s):  
Binding Sites ◽  
Molecular Mechanisms ◽  
Zinc Finger Protein ◽  
Chromatin Accessibility ◽  
Finger Protein ◽  
Genome Wide ◽  
Ipsc Generation ◽  
Cellular Identity ◽  
Induced Pluripotent ◽  
Chromatin Opening

Successful generation of induced pluripotent stem cells (iPSCs) via the overexpression of Oct4 (Pou5f1), Sox2, Klf4 and c-Myc (OSKM) highlights the power of transcription factor (TF)-mediated cellular conversions. Nevertheless, iPSC reprogramming is inherently inefficient and understanding the molecular mechanisms underlying this inefficiency holds the key to control cellular identity successfully. Here, we report 16 novel reprogramming roadblock genes identified by CRISPR/Cas9-mediated genome-wide knockout (KO) screening. Of these, disruption of KRAB zinc finger protein (KRAB-ZFP) Zfp266 strongly and consistently enhanced iPSC generation in several iPSC reprogramming settings, emerging as the most robust roadblock. Further analyses revealed that ZFP266 bound Short Interspersed Nuclear Elements (SINEs) adjacent to OSK binding sites and impedes chromatin opening. This work serves as a resource for better understanding reprogramming mechanisms and proposes SINEs as a critical genetic element that regulates chromatin accessibility at enhancers for efficient pluripotency induction.

scholarly journals RoboCOP: Jointly computing chromatin occupancy profiles for numerous factors from chromatin accessibility data

2020 ◽  
Author(s):  
Sneha Mitra ◽  
Jianling Zhong ◽  
David M. MacAlpine ◽  
Alexander J. Hartemink
Keyword(s):  
Protein Binding ◽  
Binding Sites ◽  
Protein Complexes ◽  
State Space Model ◽  
Chromatin Accessibility ◽  
Yeast Genome ◽  
Genome Wide ◽  
Dna Binding Factors ◽  
A Cell ◽  
Insight Into

AbstractChromatin is the tightly packaged structure of DNA and protein within the nucleus of a cell. The arrangement of different protein complexes along the DNA modulates and is modulated by gene expression. Measuring the binding locations and level of occupancy of different transcription factors (TFs) and nucleosomes is therefore crucial to understanding gene regulation. Antibody-based methods for assaying chromatin occupancy are capable of identifying the binding sites of specific DNA binding factors, but only one factor at a time. On the other hand, epigenomic accessibility data like ATAC-seq, DNase-seq, and MNase-seq provide insight into the chromatin landscape of all factors bound along the genome, but with minimal insight into the identities of those factors. Here, we present RoboCOP, a multivariate state space model that integrates chromatin information from epigenomic accessibility data with nucleotide sequence to compute genome-wide probabilistic scores of nucleosome and TF occupancy, for hundreds of different factors at once. We apply RoboCOP to MNase-seq data to elucidate the protein-binding landscape of nucleosomes and 150 TFs across the yeast genome. Using available protein-binding datasets from the literature, we show that our model predicts the binding of these factors genome-wide more accurately than existing methods.

scholarly journals Genome-Wide Mapping of Binding Sites Reveals Multiple Biological Functions of the Transcription Factor Cst6p in Saccharomyces cerevisiae

mBio ◽  
2016 ◽  
Vol 7 (3) ◽  
Author(s):  
Guodong Liu ◽  
David Bergenholm ◽  
Jens Nielsen
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Transcription Factor ◽  
Transcription Factors ◽  
Binding Sites ◽  
Regulatory Network ◽  
Deletion Mutant ◽  
Transcriptional Regulatory Network ◽  
Biological Processes ◽  
Genome Wide ◽  
Transcriptional Regulatory

ABSTRACT In the model eukaryote Saccharomyces cerevisiae , the transcription factor Cst6p has been reported to play important roles in several biological processes. However, the genome-wide targets of Cst6p and its physiological functions remain unknown. Here, we mapped the genome-wide binding sites of Cst6p at high resolution. Cst6p binds to the promoter regions of 59 genes with various biological functions when cells are grown on ethanol but hardly binds to the promoter at any gene when cells are grown on glucose. The retarded growth of the CST6 deletion mutant on ethanol is attributed to the markedly decreased expression of NCE103 , encoding a carbonic anhydrase, which is a direct target of Cst6p. The target genes of Cst6p have a large overlap with those of stress-responsive transcription factors, such as Sko1p and Skn7p. In addition, a CST6 deletion mutant growing on ethanol shows hypersensitivity to oxidative stress and ethanol stress, assigning Cst6p as a new member of the stress-responsive transcriptional regulatory network. These results show that mapping of genome-wide binding sites can provide new insights into the function of transcription factors and highlight the highly connected and condition-dependent nature of the transcriptional regulatory network in S. cerevisiae . IMPORTANCE Transcription factors regulate the activity of various biological processes through binding to specific DNA sequences. Therefore, the determination of binding positions is important for the understanding of the regulatory effects of transcription factors. In the model eukaryote Saccharomyces cerevisiae , the transcription factor Cst6p has been reported to regulate several biological processes, while its genome-wide targets remain unknown. Here, we mapped the genome-wide binding sites of Cst6p at high resolution. We show that the binding of Cst6p to its target promoters is condition dependent and explain the mechanism for the retarded growth of the CST6 deletion mutant on ethanol. Furthermore, we demonstrate that Cst6p is a new member of a stress-responsive transcriptional regulatory network. These results provide deeper understanding of the function of the dynamic transcriptional regulatory network in S. cerevisiae .

scholarly journals PlantRegMap: charting functional regulatory maps in plants

2019 ◽  
Author(s):  
Feng Tian ◽  
De-Chang Yang ◽  
Yu-Qi Meng ◽  
Jinpu Jin ◽  
Ge Gao
Keyword(s):  
Binding Sites ◽  
Regulatory Elements ◽  
Cis Elements ◽  
Functional Interactions ◽  
Regulatory Systems ◽  
Genome Wide ◽  
Transcriptional Regulatory ◽  
Regulatory Data ◽  
Set Up ◽  
Analysis Platform

Abstract With the goal of charting plant transcriptional regulatory maps (i.e. transcription factors (TFs), cis-elements and interactions between them), we have upgraded the TF-centred database PlantTFDB (http://planttfdb.cbi.pku.edu.cn/) to a plant regulatory data and analysis platform PlantRegMap (http://plantregmap.cbi.pku.edu.cn/) over the past three years. In this version, we updated the annotations for the previously collected TFs and set up a new section, ‘extended TF repertoires’ (TFext), to allow users prompt access to the TF repertoires of newly sequenced species. In addition to our regular TF updates, we are dedicated to updating the data on cis-elements and functional interactions between TFs and cis-elements. We established genome-wide conservation landscapes for 63 representative plants and then developed an algorithm, FunTFBS, to screen for functional regulatory elements and interactions by coupling the base-varied binding affinities of TFs with the evolutionary footprints on their binding sites. Using the FunTFBS algorithm and the conservation landscapes, we further identified over 20 million functional TF binding sites (TFBSs) and two million functional interactions for 21 346 TFs, charting the functional regulatory maps of these 63 plants. These resources are publicly available at PlantRegMap (http://plantregmap.cbi.pku.edu.cn/) and a cloud-based mirror (http://plantregmap.gao-lab.org/), providing the plant research community with valuable resources for decoding plant transcriptional regulatory systems.

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