Disordered chromatin packing regulates phenotypic plasticity

Three-dimensional supranucleosomal chromatin packing plays a profound role in modulating gene expression by regulating transcription reactions through mechanisms such as gene accessibility, binding affinities, and molecular diffusion. Here, we use a computational model that integrates disordered chromatin packing (CP) with local macromolecular crowding (MC) to study how physical factors, including chromatin density, the scaling of chromatin packing, and the size of chromatin packing domains, influence gene expression. We computationally and experimentally identify a major role of these physical factors, specifically chromatin packing scaling, in regulating phenotypic plasticity, determining responsiveness to external stressors by influencing both intercellular transcriptional malleability and heterogeneity. Applying CPMC model predictions to transcriptional data from cancer patients, we identify an inverse relationship between patient survival and phenotypic plasticity of tumor cells.

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Epigenetic Influences on Plant Responses to the Environment [University of Wisconsin - Oshkosh]

Journal of Student Research ◽

10.47611/jsr.vi.624 ◽

2019 ◽

Author(s):

Angela L Vickman ◽

Travis Smith ◽

Hayley Vandenboom ◽

Lisa A. Dorn

Keyword(s):

Gene Expression ◽

Phenotypic Plasticity ◽

Molecular Mechanisms ◽

Molecular Level ◽

Physical Structure ◽

Plant Responses ◽

Appropriate Behavior ◽

Stressful Environment ◽

University Of Wisconsin

Plants and animals may respond to changes in the environment at the molecular level by changing the amount of a gene product (a protein) to generate the appropriate behavior or physical structure (a phenotype) for that environment. For example, an extremely stressful environment can cause plants to reproduce immediately rather than waiting for conditions to improve. The molecular mechanisms for changing phenotype with environment (phenotypic plasticity) are not clear, however previous studies have shown plasticity may be the result of failing to change expression to maintain a phenotype or a deliberate change in expression altering the phenotype. To explore the molecular mechanisms underlying phenotypic plasticity, I am using a minION sequencing apparatus to re-sequence three inbred lines of Arabidopsis thaliana with extreme phenotypic plasticity differences and gene expression differences with the environment. I will specifically explore the role of methylated cytosines and adenines in gene expression.

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Disordered Chromatin Packing Regulates Ensemble Gene Expression and Phenotypic Plasticity

Biophysical Journal ◽

10.1016/j.bpj.2019.11.3005 ◽

2020 ◽

Vol 118 (3) ◽

pp. 549a-550a

Author(s):

Ranya Virk ◽

Wenli Wu ◽

Luay M. Almassalha ◽

Greta M. Bauer ◽

Yue Li ◽

...

Keyword(s):

Gene Expression ◽

Phenotypic Plasticity ◽

Chromatin Packing

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Syndecan-1 modulates the invasive potential of endometrioma via TGF-β signalling in a subgroup of women with endometriosis

Human Reproduction ◽

10.1093/humrep/deaa164 ◽

2020 ◽

Vol 35 (10) ◽

pp. 2280-2293 ◽

Cited By ~ 1

Author(s):

Sakthivignesh Ponandai-Srinivasan ◽

Merli Saare ◽

Nageswara Rao Boggavarapu ◽

Caroline Frisendahl ◽

Sophia Ehrström ◽

...

Keyword(s):

Gene Expression ◽

Ovarian Cancer ◽

Gene Silencing ◽

Three Dimensional ◽

Gene Clustering ◽

Ovarian Endometriosis ◽

Tgf Β1 ◽

3D Spheroids

Abstract STUDY QUESTION What is the physiological role of transforming growth factor-beta (TGF-β1) and syndecans (SDC1, SDC4) in endometriotic cells in women with endometriosis? SUMMARY ANSWER We observed an abnormal, pro-invasive phenotype in a subgroup of samples with ovarian endometriosis, which was reversed by combining gene silencing of SDC1 with the TGF-β1 treatment. WHAT IS KNOWN ALREADY Women with endometriosis express high levels of TGF-β1 and the proteoglycan co-receptors SDC1 and SDC4 within endometriotic cysts. However, how SDC1 and SDC4 expression is regulated by TGF-β1 and the physiological significance of the high expression in endometriotic cysts remains unknown as does the potential role in disease severity. STUDY DESIGN, SIZE, DURATION We utilized a pre-validated panel of stem- and cancer cell-associated markers on endometriotic tissue (n = 15) to stratify subgroups of women with endometriosis. Furthermore, CD90+CD73+CD105+ (SC+) endometriotic stromal cells from these patient subgroups were explored for their invasive behaviour in vitro by transient gene inhibition of SDC1 or SDC4, both in the presence or absence of TGF-β1 treatment. PARTICIPANTS/MATERIALS, SETTING, METHODS Endometriotic cyst biopsies (n = 15) were obtained from women diagnosed with ovarian endometriosis (ASRM Stage III–IV). Gene expression variability was assessed on tissue samples by applying gene clustering tools for the dataset generated from the pre-validated panel of markers. Three-dimensional (3D) spheroids from endometriotic SC+ were treated in vitro with increasing doses of TGF-β1 or the TGFBRI/II inhibitor Ly2109761 and assessed for SDC1, SDC4 expression and in vitro 3D-spheroid invasion. Transcriptomic signatures from the invaded 3D spheroids were evaluated upon combining transient gene silencing of SDC1 or SDC4, both in presence or absence of TGF-β1 treatment. Furthermore, nanoscale changes on the surface of endometriotic cells were analysed after treatment with TGF-β1 or TGFBRI/II inhibitor using atomic force microscopy. MAIN RESULTS AND THE ROLE OF CHANCE Gene clustering analysis revealed that endometriotic tissues displayed variability in their gene expression patterns; a small subgroup of samples (2/15, Endo-hi) exhibited high levels of SDC1, SDC4 and molecules involved in TGF-β signalling (TGF-β1, ESR1, CTNNB1, SNAI1, BMI1). The remaining endometriotic samples (Endo-lo) showed a uniform, low gene expression profile. Three-dimensional spheroids derived from Endo-hi SC+ but not Endo-lo SC+ samples showed an aberrant expression of SDC1 and exhibited enhanced 3D-spheroid invasion in vitro, upon rhTGF-β1 treatment. However, this abnormal, pro-invasive response of Endo-hi SC+ was reversed upon gene silencing of SDC1 with the TGF-β1 treatment. Interestingly, transcriptomic signatures of 3D spheroids silenced for SDC1 and consecutively treated with TGF-β1, showed a down-regulation of cancer-associated pathways such as WNT and GPCR signalling. LARGE SCALE DATA Transcriptomic data were deposited in NCBI’s Gene Expression Omnibus (GEO) and could be retrieved using GEO series accession number: GSE135122. LIMITATIONS, REASONS FOR CAUTION It is estimated that about 2.5% of endometriosis patients have a potential risk for developing ovarian cancer later in life. It is possible that the pro-oncogenic molecular changes observed in this cohort of endometriotic samples may not correlate with clinical occurrence of ovarian cancer later in life, thus a validation will be required. WIDER IMPLICATIONS OF THE FINDINGS This study emphasizes the importance of interactions between syndecans and TGF-β1 in the pathophysiology of endometriosis. We believe that this knowledge could be important in order to better understand endometriosis-associated complications such as ovarian cancer or infertility. STUDY FUNDING/COMPETING INTEREST(S) This study was funded by Cancerfonden (CAN 2016/696), Radiumhemmets Forskningsfonder (Project no. 154143 and 184033), EU MSCA-RISE-2015 project MOMENDO (691058), Estonian Ministry of Education and Research (IUT34-16), Enterprise Estonia (EU48695) and Karolinska Institute. Authors do not have any conflict of interest.

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The role of epigenetic regulation in adaptive phenotypic plasticity of plants

Ukrainian Botanical Journal ◽

10.15407/ukrbotj78.05.347 ◽

2021 ◽

Vol 78 (5) ◽

pp. 347-359

Author(s):

E.L. Kordyum ◽

◽

D.V. Dubyna ◽

Keyword(s):

Gene Expression ◽

Dna Methylation ◽

Phenotypic Plasticity ◽

Epigenetic Regulation ◽

Molecular Mechanisms ◽

Regulation Of Gene Expression ◽

Model Species ◽

Wide Range ◽

Adaptive Phenotypic Plasticity

In recent decades, knowledge about the role of epigenetic regulation of gene expression in plant responses to external stimuli and in adaptation of plants to adverse environmental fluctuations have extended significantly. DNA methylation is considered as the main molecular mechanism that provides genomic information and contributes to the understanding of the molecular basis of phenotypic variations based on epigenetic modifications. Unfortunately, the vast majority of research in this area has been performed on the model species Arabidopsis thaliana. The development of the methylation-sensitive amplified polymorphism (MSAP) method has made it possible to implement the large-scale detection of DNA methylation alterations in wild non-model and agricultural plants with large and highly repetitive genomes in natural and manipulated habitats. The article presents current information on DNA methylation in species of natural communities and crops and its importance in plant development and adaptive phenotypic plasticity, along with brief reviews of current ideas about adaptive phenotypic plasticity and epigenetic regulation of gene expression. The great potential of further studies of the epigenetic role in phenotypic plasticity of a wide range of non-model species in natural populations and agrocenoses for understanding the molecular mechanisms of plant existence in the changing environment in onto- and phylogeny, directly related to the key tasks of forecasting the effects of global warming and crop selection, is emphasized. Specific taxa of the Ukrainian flora, which, in authors’ opinion, are promising and interesting for this type of research, are recommended.

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Contribution of CTCF binding to transcriptional activity at the HOXA locus in NPM1-mutant AML cells

10.1101/2020.02.17.952390 ◽

2020 ◽

Author(s):

Reza Ghasemi ◽

Heidi Struthers ◽

Elisabeth R. Wilson ◽

David H. Spencer

Keyword(s):

Gene Expression ◽

Transcriptional Activity ◽

Three Dimensional ◽

Ctcf Binding ◽

Chromatin Domain ◽

Intrinsic Factors ◽

Chromatin Loops ◽

Chromatin Interactions ◽

The Common

AbstractTranscriptional regulation of the HOXA genes is thought to involve CTCF-mediated chromatin loops and the opposing actions of the COMPASS and Polycomb epigenetic complexes. We investigated the role of these mechanisms at the HOXA cluster in AML cells with the common NPM1c mutation, which express both HOXA and HOXB genes. CTCF binding at the HOXA locus is conserved across primary AML samples, regardless of HOXA gene expression, and defines a continuous chromatin domain marked by COMPASS-associated histone H3 trimethylation in NPM1-mutant primary AML samples. Profiling of the three-dimensional chromatin architecture of NPM1-mutant OCI-AML3 cells identified chromatin loops between the active HOXA9-HOXA11 genes and loci in the SNX10 gene and an intergenic region located 1.4Mbp upstream of the HOXA locus. Deletion of CTCF binding sites in OCI-AML3 cells reduced these interactions, but resulted in new, CTCF-independent loops with regions in the SKAP2 gene that were marked by enhancer-associated histone modifications in primary AML samples. HOXA gene expression was maintained in the CTCF deletion mutants, indicating that transcriptional activity at the HOXA locus in NPM1-mutant AML cells does not require long-range CTCF-mediated chromatin interactions, and instead may be driven by intrinsic factors within the HOXA gene cluster.

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Conserved patterns of alternative splicing in response to cold acclimation in fish

10.1101/429704 ◽

2018 ◽

Cited By ~ 1

Author(s):

Timothy M. Healy ◽

Patricia M. Schulte

Keyword(s):

Gene Expression ◽

Alternative Splicing ◽

Phenotypic Plasticity ◽

Cold Acclimation ◽

Gasterosteus Aculeatus ◽

Expression Patterns ◽

Functional Enrichment ◽

Cold Temperatures ◽

Qualitative Changes

AbstractPhenotypic plasticity is an important aspect of an organism’s response to environmental change that often requires the modulation of gene expression. These changes in gene expression can be quantitative as a result of increases or decreases in the amounts of specific transcripts, or qualitative as a result of the expression of alternative transcripts from the same gene (e.g., via alternative splicing of pre-mRNAs). Although the role of quantitative changes in gene expression in phenotypic plasticity is well known, relatively few studies have examined the role of qualitative changes. Here, we use skeletal muscle RNA-seq data from Atlantic killifish (Fundulus heteroclitus), threespine stickleback (Gasterosteus aculeatus) and zebrafish (Danio rerio) to investigate the extent of qualitative changes in gene expression in response to cold. Fewer genes demonstrated alternative splicing than differential expression as a result of cold acclimation; however, differences in splicing were detected for between 426 and 866 genes depending on species, indicating that large numbers of qualitative changes in gene expression are associated with cold acclimation. Many of these alternatively spliced genes were also differentially expressed, and there was functional enrichment for involvement in muscle contraction among the genes demonstrating qualitative changes in response to cold acclimation. Additionally, there was a common group of 29 genes with cold-acclimation-mediated changes in splicing in all three species, suggesting that there may be a conserved set of genes with expression patterns that respond qualitatively to prolonged cold temperatures across fishes.Summary statementQualitative changes in gene expression, such as those mediated by alternative splicing of mRNAs, are involved in phenotypic plasticity in response to prolonged cold acclimation in ectothermic animals

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ADAPTIVE DIVERGENCE BETWEEN FRESHWATER AND MARINE STICKLEBACKS: INSIGHTS INTO THE ROLE OF PHENOTYPIC PLASTICITY FROM AN INTEGRATED ANALYSIS OF CANDIDATE GENE EXPRESSION

Evolution ◽

10.1111/j.1558-5646.2009.00886.x ◽

2009 ◽

Vol 64 (4) ◽

pp. 1029-1047 ◽

Cited By ~ 97

Author(s):

R. J. Scott McCairns ◽

Louis Bernatchez

Keyword(s):

Gene Expression ◽

Phenotypic Plasticity ◽

Candidate Gene ◽

Adaptive Divergence ◽

Integrated Analysis

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Role of small nuclear RNAs in eukaryotic gene expression

Essays in Biochemistry ◽

10.1042/bse0540079 ◽

2013 ◽

Vol 54 ◽

pp. 79-90 ◽

Cited By ~ 34

Author(s):

Saba Valadkhan ◽

Lalith S. Gunawardane

Keyword(s):

Gene Expression ◽

Protein Interactions ◽

Rna Stability ◽

Splice Sites ◽

Branch Site ◽

Small Nuclear Rnas ◽

Eukaryotic Gene Expression ◽

Eukaryotic Gene ◽

Rna Biogenesis

Eukaryotic cells contain small, highly abundant, nuclear-localized non-coding RNAs [snRNAs (small nuclear RNAs)] which play important roles in splicing of introns from primary genomic transcripts. Through a combination of RNA–RNA and RNA–protein interactions, two of the snRNPs, U1 and U2, recognize the splice sites and the branch site of introns. A complex remodelling of RNA–RNA and protein-based interactions follows, resulting in the assembly of catalytically competent spliceosomes, in which the snRNAs and their bound proteins play central roles. This process involves formation of extensive base-pairing interactions between U2 and U6, U6 and the 5′ splice site, and U5 and the exonic sequences immediately adjacent to the 5′ and 3′ splice sites. Thus RNA–RNA interactions involving U2, U5 and U6 help position the reacting groups of the first and second steps of splicing. In addition, U6 is also thought to participate in formation of the spliceosomal active site. Furthermore, emerging evidence suggests additional roles for snRNAs in regulation of various aspects of RNA biogenesis, from transcription to polyadenylation and RNA stability. These snRNP-mediated regulatory roles probably serve to ensure the co-ordination of the different processes involved in biogenesis of RNAs and point to the central importance of snRNAs in eukaryotic gene expression.

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