scholarly journals Exploring functionally annotated transcriptional consensus regulatory elements with CONREL

Database ◽  
2020 ◽  
Vol 2020 ◽  
Author(s):  
Davide Dalfovo ◽  
Samuel Valentini ◽  
Alessandro Romanel
Keyword(s):  
Cell Lines ◽  
Web Application ◽  
Regulatory Networks ◽  
Regulatory Elements ◽  
Levels Of Abstraction ◽  
Binding Motifs ◽  
Extensive Collection ◽  
Transcription Factor Binding Motifs ◽  
Gene Regulatory ◽  
Genomic Regions

Abstract Understanding the interaction between human genome regulatory elements and transcription factors is fundamental to elucidate the structure of gene regulatory networks. Here we present CONREL, a web application that allows for the exploration of functionally annotated transcriptional ‘consensus’ regulatory elements at different levels of abstraction. CONREL provides an extensive collection of consensus promoters, enhancers and active enhancers for 198 cell-lines across 38 tissue types, which are also combined to provide global consensuses. In addition, 1000 Genomes Project genotype data and the ‘total binding affinity’ of thousands of transcription factor binding motifs at genomic regulatory elements is fully combined and exploited to characterize and annotate functional properties of our collection. Comparison with other available resources highlights the strengths and advantages of CONREL. CONREL can be used to explore genomic loci, specific genes or genomic regions of interest across different cell lines and tissue types. The resource is freely available at https://bcglab.cibio.unitn.it/conrel.

scholarly journals Integrative multi-omics analyses identify cell-type disease genes and regulatory networks across schizophrenia and Alzheimer’s disease

2020 ◽  
Author(s):  
Mufang Ying ◽  
Peter Rehani ◽  
Panagiotis Roussos ◽  
Daifeng Wang
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Gene Regulatory Networks ◽  
Regulatory Networks ◽  
Regulatory Elements ◽  
Disease Genes ◽  
Omics Data ◽  
Cell Type ◽  
Cellular Resolution ◽  
Gene Regulatory

AbstractStrong phenotype-genotype associations have been reported across brain diseases. However, understanding underlying gene regulatory mechanisms remains challenging, especially at the cellular level. To address this, we integrated the multi-omics data at the cellular resolution of the human brain: cell-type chromatin interactions, epigenomics and single cell transcriptomics, and predicted cell-type gene regulatory networks linking transcription factors, distal regulatory elements and target genes (e.g., excitatory and inhibitory neurons, microglia, oligodendrocyte). Using these cell-type networks and disease risk variants, we further identified the cell-type disease genes and regulatory networks for schizophrenia and Alzheimer’s disease. The celltype regulatory elements (e.g., enhancers) in the networks were also found to be potential pleiotropic regulatory loci for a variety of diseases. Further enrichment analyses including gene ontology and KEGG pathways revealed potential novel cross-disease and disease-specific molecular functions, advancing knowledge on the interplays among genetic, transcriptional and epigenetic risks at the cellular resolution between neurodegenerative and neuropsychiatric diseases. Finally, we summarized our computational analyses as a general-purpose pipeline for predicting gene regulatory networks via multi-omics data.

scholarly journals Mutations in Transcriptional Regulators Allow Selective Engineering of Signal Integration Logic

mBio ◽  
2014 ◽  
Vol 5 (3) ◽  
Author(s):  
Szabolcs Semsey
Keyword(s):  
Gene Regulatory Networks ◽  
Regulatory Networks ◽  
Regulatory Protein ◽  
Point Mutations ◽  
Building Blocks ◽  
Regulatory Elements ◽  
Regulatory Proteins ◽  
Single Amino Acid ◽  
Signal Integration ◽  
Gene Regulatory

ABSTRACT Bacterial cells monitor their environment by sensing a set of signals. Typically, these environmental signals affect promoter activities by altering the activity of transcription regulatory proteins. Promoters are often regulated by more than one regulatory protein, and in these cases the relevant signals are integrated by certain logic. In this work, we study how single amino acid substitutions in a regulatory protein (GalR) affect transcriptional regulation and signal integration logic at a set of engineered promoters. Our results suggest that point mutations in regulatory genes allow independent evolution of regulatory logic at different promoters. IMPORTANCE Gene regulatory networks are built from simple building blocks, such as promoters, transcription regulatory proteins, and their binding sites on DNA. Many promoters are regulated by more than one regulatory input. In these cases, the inputs are integrated and allow transcription only in certain combinations of input signals. Gene regulatory networks can be easily rewired, because the function of cis-regulatory elements and promoters can be altered by point mutations. In this work, we tested how point mutations in transcription regulatory proteins can affect signal integration logic. We found that such mutations allow context-dependent engineering of signal integration logic at promoters, further contributing to the plasticity of gene regulatory networks.

scholarly journals Synthetic gene-regulatory networks in the opportunistic human pathogenStreptococcus pneumoniae

2020 ◽  
Vol 117 (44) ◽  
pp. 27608-27619 ◽  
Author(s):  
Robin A. Sorg ◽  
Clement Gallay ◽  
Laurye Van Maele ◽  
Jean-Claude Sirard ◽  
Jan-Willem Veening
Keyword(s):  
Gene Expression ◽  
Virulence Factor ◽  
Gene Regulatory Networks ◽  
Regulatory Networks ◽  
Combinatorial Libraries ◽  
Regulatory Elements ◽  
Synthetic Gene ◽  
Expression Control ◽  
Gene Expression Control ◽  
Gene Regulatory

Streptococcus pneumoniaecan cause disease in various human tissues and organs, including the ear, the brain, the blood, and the lung, and thus in highly diverse and dynamic environments. It is challenging to study how pneumococci control virulence factor expression, because cues of natural environments and the presence of an immune system are difficult to simulate in vitro. Here, we apply synthetic biology methods to reverse-engineer gene expression control inS. pneumoniae. A selection platform is described that allows for straightforward identification of transcriptional regulatory elements out of combinatorial libraries. We present TetR- and LacI-regulated promoters that show expression ranges of four orders of magnitude. Based on these promoters, regulatory networks of higher complexity are assembled, such as logic AND gates and IMPLY gates. We demonstrate single-copy genome-integrated toggle switches that give rise to bimodal population distributions. The tools described here can be used to mimic complex expression patterns, such as the ones found for pneumococcal virulence factors. Indeed, we were able to rewire gene expression of the capsule operon, the main pneumococcal virulence factor, to be externally inducible (YES gate) or to act as an IMPLY gate (only expressed in absence of inducer). Importantly, we demonstrate that these synthetic gene-regulatory networks are functional in an influenza A virus superinfection murine model of pneumonia, paving the way for in vivo investigations of the importance of gene expression control on the pathogenicity ofS. pneumoniae.

scholarly journals Mapping gene regulatory networks of primary CD4+T cells using single-cell genomics and genome engineering

2019 ◽  
Author(s):  
Rachel E. Gate ◽  
Min Cheol Kim ◽  
Andrew Lu ◽  
David Lee ◽  
Eric Shifrut ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cells ◽  
Gene Regulatory Networks ◽  
Regulatory Networks ◽  
Genome Engineering ◽  
Regulatory Elements ◽  
Mapping Gene ◽  
Gene Regulatory ◽  
Novel Interactions

AbstractGene regulatory programs controlling the activation and polarization of CD4+T cells are incompletely mapped and the interindividual variability in these programs remain unknown. We sequenced the transcriptomes of ~160k CD4+T cells from 9 donors following pooled CRISPR perturbation targeting 140 regulators. We identified 134 regulators that affect T cell functionalization, includingIRF2as a positive regulator of Th2polarization. Leveraging correlation patterns between cells, we mapped 194 pairs of interacting regulators, including known (e.g.BATFandJUN) and novel interactions (e.g.ETS1andSTAT6). Finally, we identified 80 natural genetic variants with effects on gene expression, 48 of which are modified by a perturbation. In CD4+T cells, CRISPR perturbations can influencein vitropolarization and modify the effects oftransandcisregulatory elements on gene expression.

scholarly journals ATRT-07. DEFINING LOST AND GAINED TRANSCRIPTIONAL REGULATORY NETWORKS IN ATYPICAL TERATOID RHABDOID TUMOR

2021 ◽  
Vol 23 (Supplement_1) ◽  
pp. i2-i2
Author(s):  
Cody Nesvick ◽  
Liang Zhang ◽  
Alex Wixom ◽  
Feda Hamdan ◽  
Steven Johnsen ◽  
...  
Keyword(s):  
Cell Lines ◽  
Regulatory Networks ◽  
Regulatory Elements ◽  
Rhabdoid Tumor ◽  
Allelic Loss ◽  
Global Changes ◽  
Atypical Teratoid Rhabdoid Tumor ◽  
Transcriptional Regulatory Networks ◽  
Transcriptional Regulatory ◽  
Atypical Teratoid

Abstract Atypical teratoid rhabdoid tumor (ATRT) is a central nervous system cancer of infancy and early childhood that may occur anywhere along the neuraxis and is associated with a high rate of mortality. While contemporary multimodal therapeutic approaches have significantly improved overall survival, targeted therapy remains elusive, and treatment is often associated with significant morbidity. ATRT is unique in its genomic stability, with the only recurrent genetic abnormality being bi-allelic loss of the SMARCB1 gene, which encodes a core subunit of the BAF chromatin remodeling complex. The epigenetic mechanisms by which SMARCB1 loss leads to tumorigenesis are not yet well-defined and addressing this gap in understanding is necessary for creating efficacious, targeted therapeutics. To better understand the epigenetic features gained and lost in ATRT, we re-expressed SMARCB1 in a library of patient-derived and established ATRT cell lines of multiple molecular subtypes. SMARCB1 restoration significantly reduced or eliminated the proliferative and clonogenic capacity of each cell line. We performed assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-Seq) and RNA sequencing (RNA-Seq) to define putative transcriptional regulatory networks that are gained and lost in ATRT. SMARCB1 restoration was associated with global changes in chromatin openness consistent with the creation of new regulatory elements throughout the genome, and these were associated with induction of a diverse developmental transcriptional signature. Motif enrichment analysis of regions with increased accessibility defined a small but consistent number of centrally enriched transcription factor motifs across cell lines indicative of putative pioneer factors whose functions may be lost in ATRT. Pertinent chromatin immunoprecipitation with sequencing (ChIP-Seq) data will be discussed in the context of lost and gained transcriptional regulatory networks in ATRT and normal cellular development.

scholarly journals Retrotransposons spread potential cis-regulatory elements during mammary gland evolution

2019 ◽  
Author(s):  
Hidenori Nishihara
Keyword(s):  
Mammary Gland ◽  
Gene Regulatory Network ◽  
Binding Sites ◽  
Regulatory Network ◽  
Regulatory Elements ◽  
Estrogen Receptor Α ◽  
Endogenous Retrovirus ◽  
Cis Elements ◽  
Binding Motifs ◽  
Gene Regulatory

Abstract Acquisition of cis-elements is a major driving force for rewiring a gene regulatory network. Several kinds of transposable elements (TEs), mostly retrotransposons that propagate via a copy-and-paste mechanism, are known to possess transcription factor binding motifs and have provided source sequences for enhancers/promoters. However, it remains largely unknown whether retrotransposons have spread the binding sites of master regulators of morphogenesis and accelerated cis-regulatory expansion involved in common mammalian morphological features during evolution. Here, I demonstrate that thousands of binding sites for estrogen receptor α (ERα) and three related pioneer factors (FoxA1, GATA3 and AP2γ) that are essential regulators of mammary gland development arose from a spreading of the binding motifs by retrotransposons. The TE-derived functional elements serve primarily as distal enhancers and are enriched around genes associated with mammary gland morphogenesis. The source TEs occurred via a two-phased expansion consisting of mainly L2/MIR in a eutherian ancestor and endogenous retrovirus 1 (ERV1) in simian primates and murines. Thus the build-up of potential sources for cis-elements by retrotransposons followed by their frequent utilization by the host (co-option/exaptation) may have a general accelerating effect on both establishing and diversifying a gene regulatory network, leading to morphological innovation.

The Genetics of Evolutionary Novelties

2014 ◽  
Author(s):  
Günter P. Wagner
Keyword(s):  
Regulatory Networks ◽  
Molecular Mechanisms ◽  
Regulatory Elements ◽  
Complex Problem ◽  
Micro Rnas ◽  
Sex Comb ◽  
Gene Regulatory ◽  
Transcription Factor Proteins ◽  
Evolutionary Novelties

This chapter examines the molecular genetics of evolutionary novelties. In particular, it investigates which molecular mechanisms might be involved in the origination of novel gene regulatory networks (and, thus, character identity networks) and what these mechanisms imply for the origin of novel characters. The chapter begins with a discussion of the complex problem of the evolution of transcriptional regulation by focusing on the evolution of cis-regulatory elements (CREs) and the evolution of transcription factor proteins. It then asks whether novel pigment spots, such as the Drosophila wing spots, are novelties. It also explores an evolutionary novelty known as sex comb and the role of transposable elements in the origin of novel CREs. Finally, it considers the role of gene duplications, the evolution of micro-RNAs (miRNAs), and the possibility of a mechanistic difference between adaptation and innovation.

scholarly journals Layer-specific chromatin accessibility landscapes reveal regulatory networks in adult mouse visual cortex

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Lucas T Gray ◽  
Zizhen Yao ◽  
Thuc Nghi Nguyen ◽  
Tae Kyung Kim ◽  
Hongkui Zeng ◽  
...  
Keyword(s):  
Cortical Neurons ◽  
Regulatory Networks ◽  
High Throughput Sequencing ◽  
Adult Mouse ◽  
Cell Types ◽  
Regulatory Elements ◽  
Chromatin Accessibility ◽  
Binding Motifs ◽  
Mouse Cortex ◽  
Mouse Visual Cortex

Mammalian cortex is a laminar structure, with each layer composed of a characteristic set of cell types with different morphological, electrophysiological, and connectional properties. Here, we define chromatin accessibility landscapes of major, layer-specific excitatory classes of neurons, and compare them to each other and to inhibitory cortical neurons using the Assay for Transposase-Accessible Chromatin with high-throughput sequencing (ATAC-seq). We identify a large number of layer-specific accessible sites, and significant association with genes that are expressed in specific cortical layers. Integration of these data with layer-specific transcriptomic profiles and transcription factor binding motifs enabled us to construct a regulatory network revealing potential key layer-specific regulators, including Cux1/2, Foxp2, Nfia, Pou3f2, and Rorb. This dataset is a valuable resource for identifying candidate layer-specific cis-regulatory elements in adult mouse cortex.

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