GIMLET: Identifying Biological Modulators in Context-Specific Gene Regulation Using Local Energy Statistics

AbstractThe regulation of transcription factor activity dynamically changes across cellular conditions and disease subtypes. The identification of biological modulators contributing to context-specific gene regulation is one of the challenging tasks in systems biology, which is necessary to understand and control cellular responses across different genetic backgrounds and environmental conditions. Previous approaches for identifying biological modulators from gene expression data were restricted to the capturing of a particular type of a three-way dependency among a regulator, its target gene, and a modulator; these methods cannot describe the complex regulation structure, such as when multiple regulators, their target genes, and modulators are functionally related. Here, we propose a statistical method for identifying biological modulators by capturing multivariate local dependencies, based on energy statistics, which is a class of statistics based on distances. Subsequently, our method assigns a measure of statistical significance to each candidate modulator through a permutation test. We compared our approach with that of a leading competitor for identifying modulators, and illustrated its performance through both simulations and real data analysis. Our method, entitled genome-wide identification of modulators using local energy statistical test (GIMLET), is implemented with R (≥ 3.2.2) and is available from github (https://github.com/tshimam/GIMLET).

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A unique histone 3 lysine 14 chromatin signature underlies tissue-specific gene regulation

Molecular Cell ◽

10.1016/j.molcel.2021.01.041 ◽

2021 ◽

Author(s):

Isabel Regadas ◽

Olle Dahlberg ◽

Roshan Vaid ◽

Oanh Ho ◽

Sergey Belikov ◽

...

Keyword(s):

Gene Regulation ◽

Specific Gene ◽

Chromatin Signature ◽

Tissue Specific ◽

Tissue Specific Gene ◽

Histone 3

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Androgen and glucocorticoid receptor direct distinct transcriptional programs by receptor-specific and shared DNA binding sites

Nucleic Acids Research ◽

10.1093/nar/gkab185 ◽

2021 ◽

Vol 49 (7) ◽

pp. 3856-3875

Author(s):

Marina Kulik ◽

Melissa Bothe ◽

Gözde Kibar ◽

Alisa Fuchs ◽

Stefanie Schöne ◽

...

Keyword(s):

Gene Regulation ◽

Transcription Factor ◽

Dna Binding ◽

Receptor Binding ◽

Binding Sites ◽

Specific Gene ◽

Functional Diversification ◽

Enhancer Activity ◽

Sequence Composition

Abstract The glucocorticoid (GR) and androgen (AR) receptors execute unique functions in vivo, yet have nearly identical DNA binding specificities. To identify mechanisms that facilitate functional diversification among these transcription factor paralogs, we studied them in an equivalent cellular context. Analysis of chromatin and sequence suggest that divergent binding, and corresponding gene regulation, are driven by different abilities of AR and GR to interact with relatively inaccessible chromatin. Divergent genomic binding patterns can also be the result of subtle differences in DNA binding preference between AR and GR. Furthermore, the sequence composition of large regions (>10 kb) surrounding selectively occupied binding sites differs significantly, indicating a role for the sequence environment in guiding AR and GR to distinct binding sites. The comparison of binding sites that are shared shows that the specificity paradox can also be resolved by differences in the events that occur downstream of receptor binding. Specifically, shared binding sites display receptor-specific enhancer activity, cofactor recruitment and changes in histone modifications. Genomic deletion of shared binding sites demonstrates their contribution to directing receptor-specific gene regulation. Together, these data suggest that differences in genomic occupancy as well as divergence in the events that occur downstream of receptor binding direct functional diversification among transcription factor paralogs.

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Dynamic landscape of immune cell-specific gene regulation in immune-mediated diseases

Cell ◽

10.1016/j.cell.2021.03.056 ◽

2021 ◽

Author(s):

Mineto Ota ◽

Yasuo Nagafuchi ◽

Hiroaki Hatano ◽

Kazuyoshi Ishigaki ◽

Chikashi Terao ◽

...

Keyword(s):

Gene Regulation ◽

Immune Cell ◽

Specific Gene ◽

Immune Mediated ◽

Dynamic Landscape

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Identification of MEF2-regulated genes during muscle differentiation

Physiological Genomics ◽

10.1152/physiolgenomics.00149.2004 ◽

2004 ◽

Vol 20 (1) ◽

pp. 143-151 ◽

Cited By ~ 19

Author(s):

James Paris ◽

Carl Virtanen ◽

Zhibin Lu ◽

Mark Takahashi

Keyword(s):

Gene Regulation ◽

Transcription Factor ◽

Transcription Factors ◽

Neuromuscular Junctions ◽

Muscle Differentiation ◽

Signaling Cascades ◽

Specific Gene ◽

Genetic Mechanisms ◽

Selection Parameters ◽

First Time

Although a great deal has been elucidated concerning the mechanisms regulating muscle differentiation, little is known about transcription factor-specific gene regulation. Our understanding of the genetic mechanisms regulating cell differentiation is quite limited. Much of what has been defined centers on regulatory signaling cascades and transcription factors. Surprisingly few studies have investigated the association of genes with specific transcription factors. To address these issues, we have utilized a method coupling chromatin immunoprecipitation and CpG microarrays to characterize the genes associated with MEF2 in differentiating C2C12 cells. Results demonstrated a defined binding pattern over the course of differentiation. Filtered data demonstrated 9 clones to be elevated at 0 h, 792 at 6 h, 163 by 1 day, and 316 at 3 days. Using unbiased selection parameters, we selected a subset of 291 prospective candidates. Clones were sequenced and filtered for removal of redundancy between clones and for the presence of repetitive elements. We were able to place 50 of these on the mouse genome, and 20 were found to be located near well-annotated genes. From this list, previously undefined associations with MEF2 were discovered. Many of these genes represent proteins involved in neurogenesis, neuromuscular junctions, signaling and metabolism. The remaining clones include many full-length cDNA and represent novel gene targets. The results of this study provides for the first time, a unique look at gene regulation at the level of transcription factor binding in differentiating muscle.

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Hand2 Affects Neurogenesis and Cell Type-specific Gene Regulation in Neural Crest-derived Precursors of Autonomic Neurons

Microscopy and Microanalysis ◽

10.1017/s1431927607071139 ◽

2007 ◽

Vol 13 (S02) ◽

Author(s):

M Howard

Keyword(s):

Gene Regulation ◽

Neural Crest ◽

Specific Gene ◽

Cell Type ◽

Autonomic Neurons ◽

Cell Type Specific

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FIREcaller: Detecting Frequently Interacting Regions from Hi-C Data

10.1101/619288 ◽

2019 ◽

Cited By ~ 3

Author(s):

Cheynna Crowley ◽

Yuchen Yang ◽

Yunjiang Qiu ◽

Benxia Hu ◽

Armen Abnousi ◽

...

Keyword(s):

Gene Regulation ◽

Spatial Organization ◽

R Package ◽

Specific Gene ◽

List Type ◽

Cell Type ◽

R Software ◽

Computational Tools ◽

Cell Type Specific ◽

User Friendly

AbstractHi-C experiments have been widely adopted to study chromatin spatial organization, which plays an essential role in genome function. We have recently identified frequently interacting regions (FIREs) and found that they are closely associated with cell-type-specific gene regulation. However, computational tools for detecting FIREs from Hi-C data are still lacking. In this work, we present FIREcaller, a stand-alone, user-friendly R package for detecting FIREs from Hi-C data. FIREcaller takes raw Hi-C contact matrices as input, performs within-sample and cross-sample normalization, and outputs continuous FIRE scores, dichotomous FIREs, and super-FIREs. Applying FIREcaller to Hi-C data from various human tissues, we demonstrate that FIREs and super-FIREs identified, in a tissue-specific manner, are closely related to gene regulation, are enriched for enhancer-promoter (E-P) interactions, tend to overlap with regions exhibiting epigenomic signatures of cis-regulatory roles, and aid the interpretation or GWAS variants. The FIREcaller package is implemented in R and freely available at https://yunliweb.its.unc.edu/FIREcaller.Highlights– Frequently Interacting Regions (FIREs) can be used to identify tissue and cell-type-specific cis-regulatory regions.– An R software, FIREcaller, has been developed to identify FIREs and clustered FIREs into super-FIREs.

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Simultaneous trimodal single-cell measurement of transcripts, epitopes, and chromatin accessibility using TEA-seq

eLife ◽

10.7554/elife.63632 ◽

2021 ◽

Vol 10 ◽

Author(s):

Elliott Swanson ◽

Cara Lord ◽

Julian Reading ◽

Alexander T Heubeck ◽

Palak C Genge ◽

...

Keyword(s):

Gene Regulation ◽

Single Cell ◽

Human Peripheral Blood ◽

Single Cells ◽

Cell Types ◽

Chromatin Accessibility ◽

Specific Gene ◽

Test Case ◽

Cell Assays ◽

Paired Measurement

Single-cell measurements of cellular characteristics have been instrumental in understanding the heterogeneous pathways that drive differentiation, cellular responses to signals, and human disease. Recent advances have allowed paired capture of protein abundance and transcriptomic state, but a lack of epigenetic information in these assays has left a missing link to gene regulation. Using the heterogeneous mixture of cells in human peripheral blood as a test case, we developed a novel scATAC-seq workflow that increases signal-to-noise and allows paired measurement of cell surface markers and chromatin accessibility: integrated cellular indexing of chromatin landscape and epitopes, called ICICLE-seq. We extended this approach using a droplet-based multiomics platform to develop a trimodal assay that simultaneously measures transcriptomics (scRNA-seq), epitopes, and chromatin accessibility (scATAC-seq) from thousands of single cells, which we term TEA-seq. Together, these multimodal single-cell assays provide a novel toolkit to identify type-specific gene regulation and expression grounded in phenotypically defined cell types.

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Distinct expression of select and transcriptome-wide isolated 3’UTRs suggests critical roles in development and transition states

10.1101/2020.12.11.420125 ◽

2020 ◽

Author(s):

Shaoyi Ji ◽

Ze Yang ◽

Leonardi Gozali ◽

Thomas Kenney ◽

Arif Kocabas ◽

...

Keyword(s):

Gene Ontology ◽

Gene Regulation ◽

Rna Binding ◽

Rna Binding Proteins ◽

Specific Gene ◽

Coding Region ◽

Proliferating Cells ◽

Coding Regions ◽

Micro Rnas

AbstractMature mRNA molecules are typically considered to be comprised of a 5’UTR, a 3’UTR and a coding region (CDS), all attached until degradation. Unexpectedly, however, there have been multiple recent reports of widespread differential expression of mRNA 3’UTRs and their cognate coding regions, resulting in the expression of isolated 3’UTRs (i3’UTRs); these i3’UTRs can be highly expressed, often in reciprocal patterns to their cognate CDS. Similar to the role of other lncRNAs, isolated 3’UTRs are likely to play an important role in gene regulation but little is known about the contexts in which they are deployed. To begin to parse the functions of i3’UTRs, here we carry out in vitro, in vivo and in silico analyses of differential 3’UTR/CDS mRNA ratio usage across tissues, development and cell state changes both for a select list of developmentally important genes as well as through unbiased transcriptome-wide analyses. Across two developmental paradigms we find a distinct switch from high i3’UTR expression of stem cell related genes in proliferating cells compared to newly differentiated cells. Our unbiased transcriptome analysis across multiple gene sets shows that regardless of tissue, genes with high 3’UTR to CDS ratios belong predominantly to gene ontology categories related to cell-type specific functions while in contrast, the gene ontology categories of genes with low 3’UTR to CDS ratios are similar and relate to common cellular functions. In addition to these specific findings our data provide critical information from which detailed hypotheses for individual i3’UTRs can be tested-with a common theme that i3’UTRs appear poised to regulate cell-specific gene expression and state.Significance StatementThe widespread existence and expression of mRNA 3’ untranslated sequences in the absence of their cognate coding regions (called isolated 3’UTRs or i3’UTRs) opens up considerable avenues for gene regulation not previously envisioned. Each isolated 3’UTR may still bind and interact with micro RNAs, RNA binding proteins as well as other nucleic acid sequences, all in the absence or low levels of cognate protein production. Here we document the expression, localization and regulation of i3’UTRs both within particular biological systems as well as across the transcriptome. As this is an entirely new area of experimental investigation these early studies are seminal to this burgeoning field.

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