scholarly journals The SIN3A histone deacetylase complex is required for a complete transcriptional response to hypoxia

2017 ◽  
Author(s):  
Maria Tiana ◽  
Barbara Acosta-Iborra ◽  
Laura Puente-Santamaría ◽  
Pablo Hernansanz-Agustin ◽  
Rebecca Worsley-Hunt ◽  
...  
Keyword(s):  
Histone Deacetylase ◽  
Environmental Changes ◽  
Transcriptional Response ◽  
Specific Gene ◽  
Transcriptional Level ◽  
Genome Wide ◽  
Repressor Complex ◽  
Nascent Transcripts ◽  
Upregulated Genes ◽  
Transcriptional Output

ABSTRACTCells adapt to environmental changes, including fluctuations in oxygen levels, through the induction of specific gene expression programs. To identify genes regulated by hypoxia at the transcriptional level, we pulse-labeled HUVEC cells with 4-thiouridine and sequenced nascent transcripts. Then, we searched genome-wide binding profiles from the ENCODE project for factors that correlated with changes in transcription and identified binding of several components of the Sin3A co-repressor complex, including SIN3A, SAP30 and HDAC1/2, proximal to genes repressed by hypoxia.SIN3Ainterference revealed that it participates in the downregulation of 75% of the hypoxia-repressed genes in endothelial cells. Unexpectedly, it also blunted the induction of 47% of the upregulated genes, suggesting a role for this corepressor in gene induction. In agreement, ChIP-seq experiments showed that SIN3A preferentially localizes to the promoter region of actively transcribed genes and that SIN3A signal was enriched in hypoxia-repressed genes, prior exposure to the stimulus. Importantly, SINA3 occupancy was not altered by hypoxia in spite of changes in H3K27ac signal. In summary, our results reveal a prominent role for SIN3A in the transcriptional response to hypoxia and suggest a model where modulation of the associated histone deacetylase activity, rather than its recruitment, determines the transcriptional output.

scholarly journals Remodeling of Yeast Genome Expression in Response to Environmental Changes

2001 ◽  
Vol 12 (2) ◽  
pp. 323-337 ◽  
Author(s):  
Helen C. Causton ◽  
Bing Ren ◽  
Sang Seok Koh ◽  
Christopher T. Harbison ◽  
Elenita Kanin ◽  
...  
Keyword(s):  
Environmental Change ◽  
Expression Analysis ◽  
Environmental Changes ◽  
Transcriptional Response ◽  
Yeast Genome ◽  
Temperature Oxidation ◽  
Genome Wide ◽  
Environmental Responses ◽  
Yeast Genes ◽  
Response To Environmental Change

We used genome-wide expression analysis to explore how gene expression in Saccharomyces cerevisiae is remodeled in response to various changes in extracellular environment, including changes in temperature, oxidation, nutrients, pH, and osmolarity. The results demonstrate that more than half of the genome is involved in various responses to environmental change and identify the global set of genes induced and repressed by each condition. These data implicate a substantial number of previously uncharacterized genes in these responses and reveal a signature common to environmental responses that involves ∼10% of yeast genes. The results of expression analysis with MSN2/MSN4 mutants support the model that the Msn2/Msn4 activators induce the common response to environmental change. These results provide a global description of the transcriptional response to environmental change and extend our understanding of the role of activators in effecting this response.

scholarly journals Identification of a Salmonella ancillary copper detoxification mechanism by a comparative analysis of the genome-wide transcriptional response to copper and zinc excess

Microbiology ◽  
2014 ◽  
Vol 160 (8) ◽  
pp. 1659-1669 ◽  
Author(s):  
Lucas B. Pontel ◽  
Nadia L. Scampoli ◽  
Steffen Porwollik ◽  
Susana K. Checa ◽  
Michael McClelland ◽  
...  
Keyword(s):  
Metal Ions ◽  
Stress Responses ◽  
Regulatory Networks ◽  
Iron Homeostasis ◽  
Transcriptional Response ◽  
Zinc Excess ◽  
Copper And Zinc ◽  
Genome Wide ◽  
Copper Excess ◽  
Upregulated Genes

Copper and zinc are essential metal ions, but toxic in excess. Bacteria have evolved different strategies to control their intracellular concentrations, ensuring proper supply while avoiding toxicity, including the induction of metal-specific as well as non-specific mechanisms. We compared the transcriptional profiles of Salmonella Typhimurium after exposure to either copper or zinc ions in both rich and minimal media. Besides metal-specific regulatory networks many global stress-response pathways react to an excess of either of these metal ions. Copper excess affects both zinc and iron homeostasis by inducing transcription of these metal-specific regulons. In addition to the control of zinc-specific regulons, zinc excess affects the Cpx regulon and the σE envelope-stress responses. Finally, novel metal-specific upregulated genes were detected including a new copper-detoxification pathway that involves the siderophore enterobactin and the outer-membrane protein TolC. This work sheds light onto the transcriptional landscape of Salmonella after copper or zinc overload, and discloses a new mechanism of copper detoxification.

scholarly journals A Comparative Transcriptome Analysis of Rhizobium etli Bacteroids: Specific Gene Expression During Symbiotic Nongrowth

2011 ◽  
Vol 24 (12) ◽  
pp. 1553-1561 ◽  
Author(s):  
Maarten Vercruysse ◽  
Maarten Fauvart ◽  
Serge Beullens ◽  
Kristien Braeken ◽  
Lore Cloots ◽  
...  
Keyword(s):  
Stationary Phase ◽  
Specific Gene ◽  
Nitrogen Fixing ◽  
Rhizobium Etli ◽  
Transcriptome Profile ◽  
Free Living ◽  
Specific Expression ◽  
Genome Wide ◽  
Physiological Adaptations ◽  
Upregulated Genes

Rhizobium etli occurs either in a nitrogen-fixing symbiosis with its host plant, Phaseolus vulgaris, or free-living in the soil. During both conditions, the bacterium has been suggested to reside primarily in a nongrowing state. Using genome-wide transcriptome profiles, we here examine the molecular basis of the physiological adaptations of rhizobia to nongrowth inside and outside of the host. Compared with exponentially growing cells, we found an extensive overlap of downregulated growth-associated genes during both symbiosis and stationary phase, confirming the essentially nongrowing state of nitrogen-fixing bacteroids in determinate nodules that are not terminally differentiated. In contrast, the overlap of upregulated genes was limited. Generally, actively growing cells have hitherto been used as reference to analyze symbiosis-specific expression. However, this prevents the distinction between differential expression arising specifically from adaptation to a symbiotic lifestyle and features associated with nongrowth in general. Using stationary phase as the reference condition, we report a distinct transcriptome profile for bacteroids, containing 203 induced and 354 repressed genes. Certain previously described symbiosis-specific characteristics, such as the downregulation of amino acid metabolism genes, were no longer observed, indicating that these features are more likely due to the nongrowing state of bacteroids rather than representing bacteroid-specific physiological adaptations.

scholarly journals The MLL3/4 complexes and MiDAC act antagonistically as genome-wide regulators of H4K20ac to control a specific gene expression program

2021 ◽  
Author(s):  
Xiaokang Wang ◽  
Wojciech Rosikiewicz ◽  
Yurii Sedkov ◽  
Baisakhi Mondal ◽  
Satish Kallappagoudar ◽  
...  
Keyword(s):  
Gene Expression ◽  
Physiological Role ◽  
Specific Gene ◽  
Physical Interaction ◽  
Specific Gene Expression ◽  
Genome Wide ◽  
Histone H3k27 ◽  
Genomic Regions ◽  
Transcriptional Output ◽  
Expression Program

The mitotic deacetylase complex MiDAC has recently been shown to play a vital physiological role in embryonic development and neurite outgrowth. However, how MiDAC functionally intersects with other chromatin-modifying regulators is poorly understood. Here, we describe a physical interaction between the histone H3K27 demethylase UTX, a complex-specific subunit of the enhancer-associated MLL3/4 complexes, and MiDAC. We demonstrate that UTX bridges the association of the MLL3/4 complexes and MiDAC by interacting with ELMSAN1, a scaffolding subunit of MiDAC. Our data shows that MiDAC constitutes a negative genome-wide regulator of H4K20ac, an activity which is counteracted by the MLL3/4 complexes. MiDAC and the MLL3/4 complexes co-localize at many genomic regions, that are enriched for H4K20ac and the enhancer marks H3K4me1, H3K4me2 and H3K27ac. We find that MiDAC antagonizes the recruitment of the MLL3/4 complexes to negatively regulate H4K20ac, H3K4me2 and H3K27ac resulting in transcriptional attenuation of associated genes. In summary, our findings provide a paradigm how the opposing roles of chromatin-modifying components, such as MiDAC and the MLL3/4 complexes, balance the transcriptional output of specific gene expression programs.

scholarly journals Histone Deacetylase 9 Activates IKK to Regulate Atherosclerotic Plaque Vulnerability

2020 ◽  
Vol 127 (6) ◽  
pp. 811-823 ◽  
Author(s):  
Yaw Asare ◽  
Thomas A. Campbell-James ◽  
Yury Bokov ◽  
Lydia Luya Yu ◽  
Matthias Prestel ◽  
...  
Keyword(s):  
Histone Deacetylase ◽  
Atherosclerotic Plaque ◽  
Association Studies ◽  
Endothelial Activation ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Plaque Vulnerability ◽  
Plaque Stability ◽  
Genome Wide ◽  
Histone Deacetylase 9

Rationale: Arterial inflammation manifested as atherosclerosis is the leading cause of mortality worldwide. Genome-wide association studies have identified a prominent role of HDAC (histone deacetylase)-9 in atherosclerosis and its clinical complications including stroke and myocardial infarction. Objective: To determine the mechanisms linking HDAC9 to these vascular pathologies and explore its therapeutic potential for atheroprotection. Methods and Results: We studied the effects of Hdac9 on features of plaque vulnerability using bone marrow reconstitution experiments and pharmacological targeting with a small molecule inhibitor in hyperlipidemic mice. We further used 2-photon and intravital microscopy to study endothelial activation and leukocyte-endothelial interactions. We show that hematopoietic Hdac9 deficiency reduces lesional macrophage content while increasing fibrous cap thickness thus conferring plaque stability. We demonstrate that HDAC9 binds to IKK (inhibitory kappa B kinase)-α and β, resulting in their deacetylation and subsequent activation, which drives inflammatory responses in both macrophages and endothelial cells. Pharmacological inhibition of HDAC9 with the class IIa HDAC inhibitor TMP195 attenuates lesion formation by reducing endothelial activation and leukocyte recruitment along with limiting proinflammatory responses in macrophages. Transcriptional profiling using RNA sequencing revealed that TMP195 downregulates key inflammatory pathways consistent with inhibitory effects on IKKβ. TMP195 mitigates the progression of established lesions and inhibits the infiltration of inflammatory cells. Moreover, TMP195 diminishes features of plaque vulnerability and thereby enhances plaque stability in advanced lesions. Ex vivo treatment of monocytes from patients with established atherosclerosis reduced the production of inflammatory cytokines including IL (interleukin)-1β and IL-6. Conclusions: Our findings identify HDAC9 as a regulator of atherosclerotic plaque stability and IKK activation thus providing a mechanistic explanation for the prominence of HDAC9 as a vascular risk locus in genome-wide association studies. Its therapeutic inhibition may provide a potent lever to alleviate vascular inflammation. Graphical Abstract: A graphical abstract is available for this article.

scholarly journals Subtype-associated epigenomic landscape and 3D genome structure in bladder cancer

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Tejaswi Iyyanki ◽  
Baozhen Zhang ◽  
Qixuan Wang ◽  
Ye Hou ◽  
Qiushi Jin ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Transcription Factor ◽  
Cancer Cell ◽  
Genome Structure ◽  
Transcription Factor Binding ◽  
Specific Gene ◽  
Open Chromatin ◽  
Factor Binding ◽  
3D Genome ◽  
Genome Wide

Abstract Muscle-invasive bladder cancers are characterized by their distinct expression of luminal and basal genes, which could be used to predict key clinical features such as disease progression and overall survival. Transcriptionally, FOXA1, GATA3, and PPARG are shown to be essential for luminal subtype-specific gene regulation and subtype switching, while TP63, STAT3, and TFAP2 family members are critical for regulation of basal subtype-specific genes. Despite these advances, the underlying epigenetic mechanisms and 3D chromatin architecture responsible for subtype-specific regulation in bladder cancer remain unknown. Result We determine the genome-wide transcriptome, enhancer landscape, and transcription factor binding profiles of FOXA1 and GATA3 in luminal and basal subtypes of bladder cancer. Furthermore, we report the first-ever mapping of genome-wide chromatin interactions by Hi-C in both bladder cancer cell lines and primary patient tumors. We show that subtype-specific transcription is accompanied by specific open chromatin and epigenomic marks, at least partially driven by distinct transcription factor binding at distal enhancers of luminal and basal bladder cancers. Finally, we identify a novel clinically relevant transcription factor, Neuronal PAS Domain Protein 2 (NPAS2), in luminal bladder cancers that regulates other subtype-specific genes and influences cancer cell proliferation and migration. Conclusion In summary, our work identifies unique epigenomic signatures and 3D genome structures in luminal and basal urinary bladder cancers and suggests a novel link between the circadian transcription factor NPAS2 and a clinical bladder cancer subtype.

scholarly journals Absence of S100A4 in the mouse lens induces an aberrant retina-specific differentiation program and cataract

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Rupalatha Maddala ◽  
Junyuan Gao ◽  
Richard T. Mathias ◽  
Tylor R. Lewis ◽  
Vadim Y. Arshavsky ◽  
...  
Keyword(s):  
Calcium Binding ◽  
Late Onset ◽  
Cpg Islands ◽  
Transcriptome Profiling ◽  
Specific Gene ◽  
Pathway Network ◽  
S100a4 Expression ◽  
Histone H3k27 ◽  
Pathway Analyses ◽  
Upregulated Genes

AbstractS100A4, a member of the S100 family of multifunctional calcium-binding proteins, participates in several physiological and pathological processes. In this study, we demonstrate that S100A4 expression is robustly induced in differentiating fiber cells of the ocular lens and that S100A4(−/−) knockout mice develop late-onset cortical cataracts. Transcriptome profiling of lenses from S100A4(−/−) mice revealed a robust increase in the expression of multiple photoreceptor- and Müller glia-specific genes, as well as the olfactory sensory neuron-specific gene, S100A5. This aberrant transcriptional profile is characterized by corresponding increases in the levels of proteins encoded by the aberrantly upregulated genes. Ingenuity pathway network and curated pathway analyses of differentially expressed genes in S100A4(−/−) lenses identified Crx and Nrl transcription factors as the most significant upstream regulators, and revealed that many of the upregulated genes possess promoters containing a high-density of CpG islands bearing trimethylation marks at histone H3K27 and/or H3K4, respectively. In support of this finding, we further documented that S100A4(−/−) knockout lenses have altered levels of trimethylated H3K27 and H3K4. Taken together, our findings suggest that S100A4 suppresses the expression of retinal genes during lens differentiation plausibly via a mechanism involving changes in histone methylation.

scholarly journals Genome-wide association study suggests that variation at the RCOR1 locus is associated with tinnitus in UK Biobank

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Helena R. R. Wells ◽  
Fatin N. Zainul Abidin ◽  
Maxim B. Freidin ◽  
Frances M. K. Williams ◽  
Sally J. Dawson
Keyword(s):  
Association Study ◽  
Molecular Mechanisms ◽  
Genome Wide Association Study ◽  
Genome Wide Association ◽  
Uk Biobank ◽  
Significance Threshold ◽  
Genome Wide ◽  
Final Sample ◽  
Close Proximity ◽  
Repressor Complex

AbstractTinnitus is a prevalent condition in which perception of sound occurs without an external stimulus. It is often associated with pre-existing hearing loss or noise-induced damage to the auditory system. In some individuals it occurs frequently or even continuously and leads to considerable distress and difficulty sleeping. There is little knowledge of the molecular mechanisms involved in tinnitus which has hindered the development of treatments. Evidence suggests that tinnitus has a heritable component although previous genetic studies have not established specific risk factors. From a total of 172,608 UK Biobank participants who answered questions on tinnitus we performed a case–control genome-wide association study for self-reported tinnitus. Final sample size used in association analysis was N = 91,424. Three variants in close proximity to the RCOR1 gene reached genome wide significance: rs4906228 (p = 1.7E−08), rs4900545 (p = 1.8E−08) and 14:103042287_CT_C (p = 3.50E−08). RCOR1 encodes REST Corepressor 1, a component of a co-repressor complex involved in repressing neuronal gene expression in non-neuronal cells. Eleven other independent genetic loci reached a suggestive significance threshold of p < 1E−06.

scholarly journals Individuals Diagnosed with Binge-Eating Disorder Have DNA Hypomethylated Sites in Genes of the Metabolic System: A Pilot Study

Nutrients ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 1413
Author(s):  
Mariana Lizbeth Rodríguez-López ◽  
José Jaime Martínez-Magaña ◽  
David Ruiz-Ramos ◽  
Ana Rosa García ◽  
Laura Gonzalez ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Eating Disorder ◽  
Protein Kinase ◽  
Binge Eating ◽  
Binge Eating Disorder ◽  
Environmental Changes ◽  
Diagnostic Category ◽  
The Body ◽  
Metabolic System ◽  
Genome Wide

Binge-eating disorder, recently accepted as a diagnostic category, is differentiated from bulimia nervosa in that the former shows the presence of binge-eating episodes and the absence of compensatory behavior. Epigenetics is a conjunct of mechanisms (like DNA methylation) that regulate gene expression, which are dependent on environmental changes. Analysis of DNA methylation in eating disorders shows that it is reduced. The present study aimed to analyze the genome-wide DNA methylation differences between individuals diagnosed with BED and BN. A total of 46 individuals were analyzed using the Infinium Methylation EPIC array. We found 11 differentially methylated sites between BED- and BN-diagnosed individuals, with genome-wide significance. Most of the associations were found in genes related to metabolic processes (ST3GAL4, PRKAG2, and FRK), which are hypomethylated genes in BED. Cg04781532, located in the body of the PRKAG2 gene (protein kinase AMP-activated non-catalytic subunit gamma 2), was hypomethylated in individuals with BED. Agonists of PRKAG2, which is the subunit of AMPK (AMP-activated protein kinase), are proposed to treat obesity, BED, and BN. The present study contributes important insights into the effect that BED could have on PRKAG2 activation.

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