scholarly journals Multivariable regulation of gene expression plasticity in metazoans

2019 ◽  
Author(s):  
Long Xiao ◽  
Zhiguang Zhao ◽  
Fei He ◽  
Zhuo Du
Keyword(s):  
Gene Expression ◽  
Histone Modifications ◽  
Regulation Of Gene Expression ◽  
Rapid Change ◽  
High Plasticity ◽  
Expression Levels ◽  
Genome Wide ◽  
Expression Potential ◽  
Highly Correlated

ABSTRACTAn important capacity of genes is the rapid change of expression levels to cope with environment, known as expression plasticity. Elucidating the genomic mechanisms determining expression plasticity is critical for understanding the molecular basis of phenotypic plasticity, fitness, and adaptation. In this study, we systematically quantified genome-wide gene expression plasticity in four metazoan species by integrating changes of expression levels under a large number of genetic and environmental conditions. From this, we demonstrated that expression plasticity measures a distinct feature of gene expression that is orthogonal to other well-studies features including gene expression potential and tissue specificity/broadness. Expression plasticity is conserved across species with important physiological implications. The magnitude of expression plasticity is highly correlated with gene function and genes with high plasticity are implicated in disease susceptibility. Genome-wide analysis identified many conserved promoter cis-elements, trans-acting factors (such as CFCF), and gene body histone modifications (H3K36me3, H3K79me2, and H4K20me1) that are significantly associated with expression plasticity. Analysis of expression changes in perturbation experiments further validated a causal role of specific transcription factors and histone modifications. Collectively, this work reveals general properties, physiological implications, and multivariable regulation of gene expression plasticity in metazoans, extending the mechanistic understanding of gene regulation.

scholarly journals Multivariable regulation of gene expression plasticity in metazoans

Open Biology ◽  
2019 ◽  
Vol 9 (12) ◽  
pp. 190150 ◽  
Author(s):  
Long Xiao ◽  
Zhiguang Zhao ◽  
Fei He ◽  
Zhuo Du
Keyword(s):  
Gene Expression ◽  
Histone Modifications ◽  
Tissue Specificity ◽  
Regulation Of Gene Expression ◽  
Rapid Change ◽  
High Plasticity ◽  
Expression Levels ◽  
Genome Wide ◽  
Highly Correlated

An important capacity of genes is the rapid change of expression levels to cope with the environment, known as expression responsiveness or plasticity. Elucidating the genomic mechanisms determining expression plasticity is critical for understanding the molecular basis of phenotypic plasticity, fitness and adaptation. In this study, we systematically quantified gene expression plasticity in four metazoan species by integrating changes of expression levels under a large number of genetic and environmental conditions. From this, we demonstrated that expression plasticity measures a distinct feature of gene expression that is orthogonal to other well-studied features, including gene expression level and tissue specificity/broadness. Expression plasticity is conserved across species with important physiological implications. The magnitude of expression plasticity is highly correlated with gene function and genes with high plasticity are implicated in disease susceptibility. Genome-wide analysis identified many conserved promoter cis -elements, trans -acting factors (such as CTCF), and gene body histone modifications (H3K36me3, H3K79me2 and H4K20me1) that are significantly associated with expression plasticity. Analysis of expression changes in perturbation experiments further validated a causal role of specific transcription factors and histone modifications. Collectively, this work reveals the general properties, physiological implications and multivariable regulation of gene expression plasticity in metazoans, extending the mechanistic understanding of gene regulation.

scholarly journals The genome-wide role of HSF-1 in the regulation of gene expression in Caenorhabditis elegans

BMC Genomics ◽  
2016 ◽  
Vol 17 (1) ◽  
Author(s):  
Jessica Brunquell ◽  
Stephanie Morris ◽  
Yin Lu ◽  
Feng Cheng ◽  
Sandy D. Westerheide
Keyword(s):  
Gene Expression ◽  
Caenorhabditis Elegans ◽  
Regulation Of Gene Expression ◽  
Genome Wide

High Throughput Sequencing Following Cross-Linked Immune Precipitation (HITS-CLIP) of Argonaute (AGO) Identifies Mir-9 As a Regulator of MMP2 in the Marrow Microenvironment (ME)

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2392-2392 ◽  
Author(s):  
Ilango Balakrishnan ◽  
Xiaodong Yang ◽  
Beverly Torok-Storb ◽  
Jay Hesselberth ◽  
Manoj M Pillai
Keyword(s):  
Gene Expression ◽  
High Throughput ◽  
Stromal Cells ◽  
False Positive ◽  
High Throughput Sequencing ◽  
Regulation Of Gene Expression ◽  
Negative Results ◽  
Genome Wide ◽  
Direct Binding

Abstract Abstract 2392 There is increasing recognition of the role of small noncoding RNAs in post-transcriptional regulation of gene expression in diverse tissues of eukaryotic organisms including vertebrates. MicroRNAs (miRNAs) are the best studied amongst these small RNAs and are thought to act by binding to the 3' untranslated regions (3' UTRs) of mature mRNAs in a sequence-specific fashion and preventing the initiation of peptide translation and/ or initiating mRNA degradation. Recent evidence suggests that miRNA-based regulation might involve binding to regions other than 3' UTRs including coding regions. Current approaches to defining miRNA-mRNA interactions are mostly restricted to those based on bio-informatic prediction, protein down-regulation following in-vitro transfection of miRNA precursors and luciferase assays to determine binding to 3' UTRs. None of these methods however show direct interaction between a specific miRNA and its purported target RNA. Bio-informatics-based approaches are also prone to false positive and negative results given the short length of sequence matching, and reliance on heuristics and cross-species conservation. Newer genome-wide approaches like HITS-CLIP (High Throughput Sequencing following Cross Linked Immuno Precipitation, or CLIP-Seq) overcome some of these limitations by directly isolating the miRNA-mRNA interactome bound to argonaute (AGO), a critical component of the rna-induced silencing complex (RISC)1. HITS-CLIP utilizes the ability of ultraviolet (UV) light to cross-link RNAs to proteins in their close proximity. The crosslinked miRNA-mRNA-Ago complexes are then isolated and the RNA reverse transcribed to cDNA libraries and sequenced by next generation sequencing (NGS). Given the widespread role of miRNAs in several vertebrate tissues, we hypothesized that miRNA-regulation of gene expression is operant in the hematopoietic microenvironment (ME) and thus contributes to regulation of hematopoiesis. We hence used HITS-CLIP to analyze the miRNA-mRNA interactome of three key cellular components of the ME: stromal cells, endothelium and macrophages. We have previously reported on the use of the stromal cell lines Hs27a and Hs5 to define specific functional niches within the ME. Hs27a can functionally support primitive hematopoietic stem and progenitor cells (HSPC) in cobblestone areas (CSAs) and express high levels of factors known to support HSPC such as SDF1, Jagged1 and Angiopoietin1. In contrast, Hs5 drives HSPC to mature lineages and secretes high levels of cytokines like IL1, IL6 and GCSF. Human umbilical vein endothelial cells (HUVECs) and MCSF-treated CD14+ cells were utilized for the endothelial and macrophage cultures respectively. The HITS-CLIP datasets from each of these populations were enriched for a putative binding site for miR-9 in the coding region of Matrix Metalloproteinase 2 (MMP2) mRNA. MMP2 belongs to a family of endopeptidases critical in the remodeling of extracellular matrix in several tissues and in the egress/ homing of HSPC to their functional niches in the ME. Functional binding of miR-9 to MMP2 was validated by Western-blotting of stromal cells transfected with miR-9 which revealed > 50% reduction of protein levels when compared to control-transfected cells. This was also confirmed by gelatin zymography which showed significantly reduced MMP2 activity in stromal cells transfected with miR-9. Finally, to confirm direct binding of miR-9 to the putative binding region on the MMP2 transcript, we cloned this microRNA responsive region (MRE) downstream of the Renilla luciferase gene and assayed its activity by luciferase assays. MiR-9 transfection down-regulated luciferase activity > 50% confirming direct binding to the MRE. Our results show that genome-wide approaches such as HITS-CLIP can be used to define in vivo miRNA-mRNA interactions in the ME and should be considered in studies that define such interactions given the significant false-positive and false negative results associated with approaches based on bio-informatics alone. The approach can also define specific interactions between miRNAs and mRNAs such as MMP2, of relevance to regulation of the hematopoietic ME. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Chromatin is an ancient innovation conserved between Archaea and Eukarya

eLife ◽  
2012 ◽  
Vol 1 ◽  
Author(s):  
Ron Ammar ◽  
Dax Torti ◽  
Kyle Tsui ◽  
Marinella Gebbia ◽  
Tanja Durbic ◽  
...  
Keyword(s):  
Gene Expression ◽  
Chromatin Structure ◽  
Nucleosome Occupancy ◽  
Regulation Of Gene Expression ◽  
Haloferax Volcanii ◽  
Dna Compaction ◽  
Genome Wide ◽  
Eukaryotic Chromatin ◽  
Transcriptional Start Sites

The eukaryotic nucleosome is the fundamental unit of chromatin, comprising a protein octamer that wraps ∼147 bp of DNA and has essential roles in DNA compaction, replication and gene expression. Nucleosomes and chromatin have historically been considered to be unique to eukaryotes, yet studies of select archaea have identified homologs of histone proteins that assemble into tetrameric nucleosomes. Here we report the first archaeal genome-wide nucleosome occupancy map, as observed in the halophile Haloferax volcanii. Nucleosome occupancy was compared with gene expression by compiling a comprehensive transcriptome of Hfx. volcanii. We found that archaeal transcripts possess hallmarks of eukaryotic chromatin structure: nucleosome-depleted regions at transcriptional start sites and conserved −1 and +1 promoter nucleosomes. Our observations demonstrate that histones and chromatin architecture evolved before the divergence of Archaea and Eukarya, suggesting that the fundamental role of chromatin in the regulation of gene expression is ancient.

scholarly journals Ctcf Haploinsufficiency Mediates Intron Retention in A Tissue-specific Manner

2019 ◽  
Author(s):  
Adel B Alharbi ◽  
Ulf Schmitz ◽  
Amy D Marshall ◽  
Darya Vanichkina ◽  
Rajini Nagarajah ◽  
...  
Keyword(s):  
Gene Expression ◽  
Intron Retention ◽  
Regulation Of Gene Expression ◽  
Splicing Factors ◽  
Tissue Specific ◽  
Genome Wide ◽  
Liver And Kidney ◽  
Specific Regulation ◽  
Dose Dependent

AbstractCTCF is a master regulator of gene transcription and chromatin organization with occupancy at thousands of DNA target sites. CTCF is essential for embryonic development and somatic cell viability and has been characterized as a haploinsufficient tumor suppressor. Increasing evidence demonstrates CTCF as a key player in several alternative splicing (AS) regulatory mechanisms, including transcription elongation, regulation of splicing factors, and epigenetic regulation. However, the genome-wide impact of Ctcf dosage on AS has not been investigated. We examined the effect of Ctcf haploinsufficiency on gene expression and AS in multiple tissues from Ctcf hemizygous (Ctcf+/-) mice. Distinct tissue-specific differences in gene expression and AS were observed in Ctcf+/- mice compared to wildtype mice. We observed a surprisingly large number of increased intron retention (IR) events in Ctcf+/- liver and kidney, specifically in genes associated with cytoskeletal organization, splicing and metabolism. This study provides further evidence for Ctcf dose-dependent and tissue-specific regulation of gene expression and AS. Our data provide a strong foundation for elucidating the mechanistic role of CTCF in AS regulation and its biological consequences.

scholarly journals CarD contributes to diverse gene expression outcomes throughout the genome ofMycobacterium tuberculosis

2019 ◽  
Vol 116 (27) ◽  
pp. 13573-13581 ◽  
Author(s):  
Dennis X. Zhu ◽  
Ashley L. Garner ◽  
Eric A. Galburt ◽  
Christina L. Stallings
Keyword(s):  
Gene Expression ◽  
Transcriptional Repression ◽  
Transcription Initiation ◽  
Regulation Of Gene Expression ◽  
Kinetic Properties ◽  
E Coli ◽  
Promoter Escape ◽  
Genome Wide ◽  
Intrinsic Kinetic

The ability to regulate gene expression through transcription initiation underlies the adaptability and survival of all bacteria. Recent work has revealed that the transcription machinery in many bacteria diverges from the paradigm that has been established inEscherichia coli.Mycobacterium tuberculosis(Mtb) encodes the RNA polymerase (RNAP)-binding protein CarD, which is absent inE. colibut is required to form stable RNAP-promoter open complexes (RPo) and is essential for viability inMtb. The stabilization of RPoby CarD has been proposed to result in activation of gene expression; however, CarD has only been examined on limited promoters that do not represent the typical promoter structure inMtb. In this study, we investigate the outcome of CarD activity on gene expression fromMtbpromoters genome-wide by performing RNA sequencing on a panel of mutants that differentially affect CarD’s ability to stabilize RPo. In all CarD mutants, the majority ofMtbprotein encoding transcripts were differentially expressed, demonstrating that CarD had a global effect on gene expression. Contrary to the expected role of CarD as a transcriptional activator, mutation of CarD led to both up- and down-regulation of gene expression, suggesting that CarD can also act as a transcriptional repressor. Furthermore, we present evidence that stabilization of RPoby CarD could lead to transcriptional repression by inhibiting promoter escape, and the outcome of CarD activity is dependent on the intrinsic kinetic properties of a given promoter region. Collectively, our data support CarD’s genome-wide role of regulating diverse transcription outcomes.

scholarly journals Chromatin profiling of the repetitive and non-repetitive genome of the human fungal pathogen Candida albicans

2018 ◽  
Author(s):  
Robert Jordan Price ◽  
Esther Weindling ◽  
Judith Berman ◽  
Alessia Buscaino
Keyword(s):  
Gene Expression ◽  
Candida Albicans ◽  
Histone Modifications ◽  
Chromatin Structure ◽  
Fungal Pathogen ◽  
Genome Stability ◽  
Regulation Of Gene Expression ◽  
Rdna Locus ◽  
Genome Wide ◽  
Chromatin Profiling

ABSTRACTBackgroundEukaryotic genomes are packaged into chromatin structures with pivotal roles in regulating all DNA-associated processes. Post-translational modifications of histone proteins modulate chromatin structure leading to rapid, reversible regulation of gene expression and genome stability which are key steps in environmental adaptation. Candida albicans is the leading fungal pathogen in humans, and can rapidly adapt and thrive in diverse host niches. The contribution of chromatin to C. albicans biology is largely unexplored.ResultsHere, we harnessed genome-wide sequencing approaches to generate the first comprehensive chromatin profiling of histone modifications (H3K4me3, H3K9Ac, H4K16Ac and γ-H2A) across the C. albicans genome and relate it to gene expression. We demonstrate that gene-rich non-repetitive regions are packaged in canonical euchromatin associated with histone modifications that mirror their transcriptional activity. In contrast, repetitive regions are assembled into distinct chromatin states: subtelomeric regions and the rDNA locus are assembled into canonical heterochromatin, while Major Repeat Sequences and transposons are packaged in chromatin bearing features of euchromatin and heterochromatin. Genome-wide mapping of γH2A, a marker of genome instability, allowed the identification of potential recombination-prone genomic sites. Finally, we present the first quantitative chromatin profiling in C. albicans to delineate the role of the chromatin modifiers Sir2 and Set1 in controlling chromatin structure and gene expression.ConclusionsThis study presents the first genome-wide chromatin profiling of histone modifications associated with the C. albicans genome. These epigenomic maps provide an invaluable resource to understand the contribution of chromatin to C. albicans biology.

scholarly journals Genome-Wide Expression and Alternative Splicing in Domesticated Sunflowers (Helianthus annuus L.) under Flooding Stress

Agronomy ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. 92
Author(s):  
Joon Seon Lee ◽  
Lexuan Gao ◽  
Laura Melissa Guzman ◽  
Loren H. Rieseberg
Keyword(s):  
Gene Expression ◽  
Alternative Splicing ◽  
Mixed Model ◽  
Agricultural Land ◽  
Alcohol Fermentation ◽  
Expression Levels ◽  
Flooding Stress ◽  
Genome Wide ◽  
And Control ◽  
Gene Expression Levels

Approximately 10% of agricultural land is subject to periodic flooding, which reduces the growth, survivorship, and yield of most crops, reinforcing the need to understand and enhance flooding resistance in our crops. Here, we generated RNA-Seq data from leaf and root tissue of domesticated sunflower to explore differences in gene expression and alternative splicing (AS) between a resistant and susceptible cultivar under both flooding and control conditions and at three time points. Using a combination of mixed model and gene co-expression analyses, we were able to separate general responses of sunflower to flooding stress from those that contribute to the greater tolerance of the resistant line. Both cultivars responded to flooding stress by upregulating expression levels of known submergence responsive genes, such as alcohol dehydrogenases, and slowing metabolism-related activities. Differential AS reinforced expression differences, with reduced AS frequencies typically observed for genes with upregulated expression. Significant differences were found between the genotypes, including earlier and stronger upregulation of the alcohol fermentation pathway and a more rapid return to pre-flooding gene expression levels in the resistant genotype. Our results show how changes in the timing of gene expression following both the induction of flooding and release from flooding stress contribute to increased flooding tolerance.

Speciation and changes in male gene expression in Drosophila

Genome ◽  
2020 ◽  
pp. 1-11
Author(s):  
Bahar Patlar ◽  
Alberto Civetta
Keyword(s):  
Gene Expression ◽  
Reproductive Isolation ◽  
Potential Role ◽  
Regulation Of Gene Expression ◽  
Drosophila Model ◽  
Depth Analysis ◽  
The Impact ◽  
Plastic Responses ◽  
Male Gene

It has long been acknowledged that changes in the regulation of gene expression may account for major organismal differences. However, we still do not fully understand how changes in gene expression evolve and how do such changes influence organisms’ differences. We are even less aware of the impact such changes might have in restricting gene flow between species. Here, we focus on studies of gene expression and speciation in the Drosophila model. We review studies that have identified gene interactions in post-mating reproductive isolation and speciation, particularly those that modulate male gene expression. We also address studies that have experimentally manipulated changes in gene expression to test their effect in post-mating reproductive isolation. We highlight the need for a more in-depth analysis of the role of selection causing disrupted gene expression of such candidate genes in sterile/inviable hybrids. Moreover, we discuss the relevance to incorporate more routinely assays that simultaneously evaluate the potential effects of environmental factors and genetic background in modulating plastic responses in male genes and their potential role in speciation.

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