Reduced chromatin accessibility underlies gene expression differences in homologous chromosome arms of diploid Aegilops tauschii and hexaploid wheat

Abstract Background Polyploidy is centrally important in the evolution and domestication of plants because it leads to major genomic changes, such as altered patterns of gene expression, which are thought to underlie the emergence of new traits. Despite the common occurrence of these globally altered patterns of gene expression in polyploids, the mechanisms involved are not well understood. Results Using a precisely defined framework of highly conserved syntenic genes on hexaploid wheat chromosome 3DL and its progenitor 3 L chromosome arm of diploid Aegilops tauschii, we show that 70% of these gene pairs exhibited proportionately reduced gene expression, in which expression in the hexaploid context of the 3DL genes was ∼40% of the levels observed in diploid Ae tauschii. Several genes showed elevated expression during the later stages of grain development in wheat compared with Ae tauschii. Gene sequence and methylation differences probably accounted for only a few cases of differences in gene expression. In contrast, chromosome-wide patterns of reduced chromatin accessibility of genes in the hexaploid chromosome arm compared with its diploid progenitor were correlated with both reduced gene expression and the imposition of new patterns of gene expression. Conclusions Our pilot-scale analyses show that chromatin compaction may orchestrate reduced gene expression levels in the hexaploid chromosome arm of wheat compared to its diploid progenitor chromosome arm.

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Reduced chromatin accessibility underlies gene expression differences in homologous chromosome arms of hexaploid wheat and diploidAegilops tauschii

10.1101/571133 ◽

2019 ◽

Cited By ~ 3

Author(s):

Fu-Hao Lu ◽

Neil McKenzie ◽

Laura-Jayne Gardiner ◽

Ming-Cheng Luo ◽

Anthony Hall ◽

...

Keyword(s):

Gene Expression ◽

Hexaploid Wheat ◽

Large Scale ◽

Aegilops Tauschii ◽

Wheat Chromosome ◽

Chromatin Accessibility ◽

Chromosome Arm ◽

Elevated Expression ◽

Differential Gene ◽

Altered Gene

AbstractPolyploidy has been centrally important in driving the evolution of plants, and leads to alterations in gene expression that are thought to underlie the emergence of new traits. Despite the common occurrence of these global patterns of altered gene expression in polyploids, the mechanisms involved are not well understood. Using a precise framework of highly conserved syntenic genes on hexaploid wheat chromosome 3DL and its progenitor 3L chromosome arm of diploidAegilops tauschii, we show that 70% of these genes exhibited proportionally reduced gene expression, in which expression in the hexaploid context of the 3DL genes was approximately 40% of the levels observed in diploidAe. tauschii.Many genes showing elevated expression during later stages of grain development in wheat compared toAe. tauschii.Gene sequence and methylation differences accounted for only a few cases of differences in gene expression. In contrast, large scale patterns of reduced chromatin accessibility of genes in the hexaploid chromosome arm compared to its diploid progenitor were correlated with observed overall reduction in gene expression and differential gene expression. Therefore, that an overall reduction in accessible chromatin underlies the major differences in gene expression that results from polyploidization.

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Phenotypic and molecular characterization of Hessian fly resistance in diploid wheat, Aegilops tauschii

BMC Plant Biology ◽

10.1186/s12870-019-2058-6 ◽

2019 ◽

Vol 19 (1) ◽

Author(s):

Jill A. Nemacheck ◽

Brandon J. Schemerhorn ◽

Steven R. Scofield ◽

Subhashree Subramanyam

Keyword(s):

Genetic Resources ◽

Molecular Characterization ◽

Hexaploid Wheat ◽

Aegilops Tauschii ◽

Hessian Fly ◽

Functional Validation ◽

Diploid Progenitor ◽

Molecular Responses ◽

Physical Measurements

Abstract Background The Hessian fly (Mayetiola destructor), belonging to the gall midge family (Cecidomyiidae), is a devastating pest of wheat (Triticum aestivum) causing significant yield losses. Despite identification and characterization of numerous Hessian fly-responsive genes and associated biological pathways involved in wheat defense against this dipteran pest, their functional validation has been challenging. This is largely attributed to the large genome, polyploidy, repetitive DNA, and limited genetic resources in hexaploid wheat. The diploid progenitor Aegilops tauschii, D-genome donor of modern-day hexaploid wheat, offers an ideal surrogate eliminating the need to target all three homeologous chromosomes (A, B and D) individually, and thereby making the functional validation of candidate Hessian fly-responsive genes plausible. Furthermore, the well-annotated sequence of Ae. tauschii genome and availability of genetic resources amenable to manipulations makes the functional assays less tedious and time-consuming. However, prior to utilization of this diploid genome for downstream studies, it is imperative to characterize its physical and molecular responses to Hessian fly. Results In this study we screened five Ae. tauschii accessions for their response to the Hessian fly biotypes L and vH13. Two lines were identified that exhibited a homozygous resistance response to feeding by both Hessian fly biotypes. Studies using physical measurements and neutral red staining showed that the resistant Ae. tauschii accessions resembled hexaploid wheat in their phenotypic responses to Hessian fly, that included similarities in larval developmental stages, leaf and plant growth, and cell wall permeability. Furthermore, molecular responses, characterized by gene expression profiling using quantitative real-time PCR, in select resistant Ae. tauschii lines also revealed similarities with resistant hexaploid wheat. Conclusions Phenotypic and molecular characterization of Ae. tauschii to Hessian fly infestation revealed resistant accessions that shared similarities to hexaploid wheat. Resembling the resistant hexaploid wheat, the Ae. tauschii accessions mount an early defense strategy involving defense proteins including lectins, secondary metabolites and reactive oxygen species (ROS) radicals. Our results reveal the suitability of the diploid progenitor for use as an ideal tool for functional genomics research in deciphering the wheat-Hessian fly molecular interactions.

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Transcriptome Analysis of Hypertrophic Heart Tissues from Murine Transverse Aortic Constriction and Human Aortic Stenosis Reveals Key Genes and Transcription Factors Involved in Cardiac Remodeling Induced by Mechanical Stress

Disease Markers ◽

10.1155/2019/5058313 ◽

2019 ◽

Vol 2019 ◽

pp. 1-10

Author(s):

Peng Yu ◽

Baoli Zhang ◽

Ming Liu ◽

Ying Yu ◽

Ji Zhao ◽

...

Keyword(s):

Gene Expression ◽

Transcription Factors ◽

Aortic Stenosis ◽

Mechanical Stress ◽

Cardiac Remodeling ◽

Interaction Network ◽

Cytokine Signaling ◽

Transverse Aortic Constriction ◽

Aortic Constriction ◽

Genomic Changes

Background. Mechanical stress-induced cardiac remodeling that results in heart failure is characterized by transcriptional reprogramming of gene expression. However, a systematic study of genomic changes involved in this process has not been performed to date. To investigate the genomic changes and underlying mechanism of cardiac remodeling, we collected and analyzed DNA microarray data for murine transverse aortic constriction (TAC) and human aortic stenosis (AS) from the Gene Expression Omnibus database and the European Bioinformatics Institute. Methods and Results. The differential expression genes (DEGs) across the datasets were merged. The Venn diagrams showed that the number of intersections for early and late cardiac remodeling was 74 and 16, respectively. Gene ontology and protein–protein interaction network analysis showed that metabolic changes, cell differentiation and growth, cell cycling, and collagen fibril organization accounted for a great portion of the DEGs in the TAC model, while in AS patients’ immune system signaling and cytokine signaling displayed the most significant changes. The intersections between the TAC model and AS patients were few. Nevertheless, the DEGs of the two species shared some common regulatory transcription factors (TFs), including SP1, CEBPB, PPARG, and NFKB1, when the heart was challenged by applied mechanical stress. Conclusions. This study unravels the complex transcriptome profiles of the heart tissues and highlighting the candidate genes involved in cardiac remodeling induced by mechanical stress may usher in a new era of precision diagnostics and treatment in patients with cardiac remodeling.

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Mapping chromatin accessibility and active regulatory elements reveals pathological mechanisms in human gliomas

Nature Communications ◽

10.1038/s41467-021-23922-2 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Karolina Stępniak ◽

Magdalena A. Machnicka ◽

Jakub Mieczkowski ◽

Anna Macioszek ◽

Bartosz Wojtaś ◽

...

Keyword(s):

Gene Expression ◽

Chromatin Structure ◽

Molecular Mechanisms ◽

Genome Mapping ◽

Malignant Gliomas ◽

Regulatory Elements ◽

Chromatin Accessibility ◽

Multiple Tumor ◽

Genes Encoding ◽

Methylation Patterns

AbstractChromatin structure and accessibility, and combinatorial binding of transcription factors to regulatory elements in genomic DNA control transcription. Genetic variations in genes encoding histones, epigenetics-related enzymes or modifiers affect chromatin structure/dynamics and result in alterations in gene expression contributing to cancer development or progression. Gliomas are brain tumors frequently associated with epigenetics-related gene deregulation. We perform whole-genome mapping of chromatin accessibility, histone modifications, DNA methylation patterns and transcriptome analysis simultaneously in multiple tumor samples to unravel epigenetic dysfunctions driving gliomagenesis. Based on the results of the integrative analysis of the acquired profiles, we create an atlas of active enhancers and promoters in benign and malignant gliomas. We explore these elements and intersect with Hi-C data to uncover molecular mechanisms instructing gene expression in gliomas.

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Leveraging epigenetics to enhance the efficacy of immunotherapy

Clinical Epigenetics ◽

10.1186/s13148-021-01100-x ◽

2021 ◽

Vol 13 (1) ◽

Author(s):

Jonathan D. Licht ◽

Richard L. Bennett

Keyword(s):

Gene Expression ◽

Clinical Trials ◽

Antigen Presentation ◽

Tumor Cells ◽

Immune Evasion ◽

Regulatory Elements ◽

Chromatin Accessibility ◽

Epigenetic Modifications ◽

Main Body ◽

Epigenetic Mechanisms

Abstract Background Epigenetic mechanisms regulate chromatin accessibility patterns that govern interaction of transcription machinery with genes and their cis-regulatory elements. Mutations that affect epigenetic mechanisms are common in cancer. Because epigenetic modifications are reversible many anticancer strategies targeting these mechanisms are currently under development and in clinical trials. Main body Here we review evidence suggesting that epigenetic therapeutics can deactivate immunosuppressive gene expression or reprogram tumor cells to activate antigen presentation mechanisms. In addition, the dysregulation of epigenetic mechanisms commonly observed in cancer may alter the immunogenicity of tumor cells and effectiveness of immunotherapies. Conclusions Therapeutics targeting epigenetic mechanisms may be helpful to counter immune evasion and improve the effectiveness of immunotherapies.

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Gene expression-based biomarkers designating glioblastomas resistant to multiple treatment strategies

Carcinogenesis ◽

10.1093/carcin/bgab024 ◽

2021 ◽

Author(s):

Otília Menyhárt ◽

János Tibor Fekete ◽

Balázs Győrffy

Keyword(s):

Gene Expression ◽

Treatment Strategies ◽

Area Under The Curve ◽

Predictive Biomarkers ◽

Subsequent Treatment ◽

Survival Status ◽

Multiple Treatment ◽

Post Surgery ◽

Potential Biomarker ◽

Elevated Expression

Abstract Despite advances in molecular characterization of glioblastoma multiforme (GBM), only a handful of predictive biomarkers exist with limited clinical relevance. We aimed to identify differentially expressed genes in tumor samples collected at surgery associated with response to subsequent treatment, including temozolomide (TMZ) and nitrosoureas. Gene expression was collected from multiple independent datasets. Patients were categorized as responders/nonresponders based on their survival status at 16 months post-surgery. For each gene, the expression was compared between responders and nonresponders with a Mann-Whitney U test and receiver operating characteristic. The package "roc" was used to calculate the area under the curve (AUC). The integrated database comprises 454 GBM patients from three independent datasets and 10,103 genes. The highest proportion of responders (68%) were among patients treated with TMZ combined with nitrosoureas, where FCGR2B upregulation provided the strongest predictive value (AUC=0.72, p < 0.001). Elevated expression of CSTA and MRPS17 was associated with a lack of response to multiple treatment strategies. DLL3 upregulation was present in subsequent responders to any treatment combination containing TMZ. Three genes (PLSCR1, MX1, and MDM2) upregulated both in the younger cohort and in patients expressing low MGMT delineate a subset of patients with worse prognosis within a population generally associated with a favorable outcome. The identified transcriptomic changes provide biomarkers of responsiveness, offer avenues for preclinical studies, and may enhance future GBM patient stratifications. The described methodology provides a reliable pipeline for the initial testing of potential biomarker candidates for future validation studies.

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The AML-associated K313 mutation enhances C/EBPα activity by leading to C/EBPα overexpression

Cell Death and Disease ◽

10.1038/s41419-021-03948-6 ◽

2021 ◽

Vol 12 (7) ◽

Author(s):

Ian Edward Gentle ◽

Isabel Moelter ◽

Mohamed Tarek Badr ◽

Konstanze Döhner ◽

Michael Lübbert ◽

...

Keyword(s):

Gene Expression ◽

Cell Culture ◽

Transcription Factor ◽

Transcription Factors ◽

Transcriptional Activity ◽

Target Gene ◽

Wild Type ◽

Elevated Expression ◽

Factor C ◽

Acute Myeloid

AbstractMutations in the transcription factor C/EBPα are found in ~10% of all acute myeloid leukaemia (AML) cases but the contribution of these mutations to leukemogenesis is incompletely understood. We here use a mouse model of granulocyte progenitors expressing conditionally active HoxB8 to assess the cell biological and molecular activity of C/EBPα-mutations associated with human AML. Both N-terminal truncation and C-terminal AML-associated mutations of C/EBPα substantially altered differentiation of progenitors into mature neutrophils in cell culture. Closer analysis of the C/EBPα-K313-duplication showed expansion and prolonged survival of mutant C/EBPα-expressing granulocytes following adoptive transfer into mice. C/EBPα-protein containing the K313-mutation further showed strongly enhanced transcriptional activity compared with the wild-type protein at certain promoters. Analysis of differentially regulated genes in cells overexpressing C/EBPα-K313 indicates a strong correlation with genes regulated by C/EBPα. Analysis of transcription factor enrichment in the differentially regulated genes indicated a strong reliance of SPI1/PU.1, suggesting that despite reduced DNA binding, C/EBPα-K313 is active in regulating target gene expression and acts largely through a network of other transcription factors. Strikingly, the K313 mutation caused strongly elevated expression of C/EBPα-protein, which could also be seen in primary K313 mutated AML blasts, explaining the enhanced C/EBPα activity in K313-expressing cells.

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The regulatory genome of the malaria vector Anopheles gambiae: integrating chromatin accessibility and gene expression

NAR Genomics and Bioinformatics ◽

10.1093/nargab/lqaa113 ◽

2021 ◽

Vol 3 (1) ◽

Author(s):

José L Ruiz ◽

Lisa C Ranford-Cartwright ◽

Elena Gómez-Díaz

Keyword(s):

Gene Expression ◽

Transcriptional Regulation ◽

Anopheles Gambiae ◽

Mosquito Control ◽

Regulatory Elements ◽

Chromatin Accessibility ◽

Malaria Vectors ◽

Specific Gene ◽

Mosquito Vector ◽

Human Malaria

Abstract Anopheles gambiae mosquitoes are primary human malaria vectors, but we know very little about their mechanisms of transcriptional regulation. We profiled chromatin accessibility by the assay for transposase-accessible chromatin by sequencing (ATAC-seq) in laboratory-reared A. gambiae mosquitoes experimentally infected with the human malaria parasite Plasmodium falciparum. By integrating ATAC-seq, RNA-seq and ChIP-seq data, we showed a positive correlation between accessibility at promoters and introns, gene expression and active histone marks. By comparing expression and chromatin structure patterns in different tissues, we were able to infer cis-regulatory elements controlling tissue-specific gene expression and to predict the in vivo binding sites of relevant transcription factors. The ATAC-seq assay also allowed the precise mapping of active regulatory regions, including novel transcription start sites and enhancers that were annotated to mosquito immune-related genes. Not only is this study important for advancing our understanding of mechanisms of transcriptional regulation in the mosquito vector of human malaria, but the information we produced also has great potential for developing new mosquito-control and anti-malaria strategies.

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Evaluation of Triticum durum–Aegilops tauschii derived primary synthetics as potential sources of heat stress tolerance for wheat improvement

Plant Genetic Resources ◽

10.1017/s1479262121000113 ◽

2021 ◽

Vol 19 (1) ◽

pp. 74-89

Author(s):

Amandeep Kaur ◽

Parveen Chhuneja ◽

Puja Srivastava ◽

Kuldeep Singh ◽

Satinder Kaur

Keyword(s):

Heat Stress ◽

Stress Tolerance ◽

Hexaploid Wheat ◽

Aegilops Tauschii ◽

Grain Filling ◽

World Population ◽

Potential Candidate ◽

Terminal Heat Stress ◽

Heat Stress Tolerance ◽

The Impact

AbstractAddressing the impact of heat stress during flowering and grain filling is critical to sustaining wheat productivity to meet a steadily increasing demand from a rapidly growing world population. Crop wild progenitor species of wheat possess a wealth of genetic diversity for several biotic and abiotic stresses, and morphological traits and can serve as valuable donors. The transfer of useful variation from the diploid progenitor, Aegilops tauschii, to hexaploid wheat can be done through the generation of synthetic hexaploid wheat (SHW). The present study targeted the identification of potential primary SHWs to introduce new genetic variability for heat stress tolerance. Selected SHWs were screened for different yield-associated traits along with three advanced breeding lines and durum parents as checks for assessing terminal heat stress tolerance under timely and late sown conditions for two consecutive seasons. Heat tolerance index based on the number of productive tillers and thousand grain weight indicated that three synthetics, syn9809 (64.32, 78.80), syn14128 (50.30, 78.28) and syn14135 (58.16, 76.03), were able to endure terminal heat stress better than other SHWs as well as checks. One of these synthetics, syn14128, recorded a minimum reduction in thousand kernel weight (21%), chlorophyll content (2.56%), grain width (1.07%) despite minimum grain-filling duration (36.15 d) and has been selected as a potential candidate for introducing the terminal heat stress tolerance in wheat breeding programmes. Breeding efforts using these candidate donors will help develop lines with a higher potential to express the desired heat stress-tolerant phenotype under field conditions.

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