Histone deacetylase inhibition leads to regulatory histone mark alterations and impairs meiosis in oocytes

Abstract Background Panobinostat (PB), a histone deacetylase (HDAC) inhibitor drug, is clinically used in the treatment of cancers. We investigated the effects of PB on murine ovarian functions in embryos and adult animals. Methods C57BL/6J mice were treated with 5 mg/kg PB on alternate days from embryonic day (E) 6.5 to E15.5. We analysed the effects of PB on the ovaries by using immunofluorescence, gene expression analysis and DNA methylation analysis techniques. Results At E15.5, we observed increases in histone H3K9Ac, H4Ac and H3K4me3 marks, while the level of the silencing H3K9me3 mark decreased. Synaptonemal complex examination at E15.5, E17.5 and E18.5 showed a delay in meiotic progression characterized by the absence of synaptonemal complexes at E15.5 and the persistence of double-strand breaks (DSBs) at E17.5 and E18.5 in PB-exposed oocytes. We found that exposure to PB led to changes in the expression of 1169 transcripts at E15.5. Genes regulated by the male-specific factors SRY-Box Transcription Factor 9 (SOX9) and Doublesex and Mab-3-related Transcription factor 1 (DMRT1) were among the most upregulated genes in the ovaries of PB-exposed mice. In contrast, PB treatment led to decreases in the expression of genes regulated by the WNT4 pathway. Notably, we observed 119 deregulated genes encoding Zn-finger proteins. The observed alterations in epigenetic marks and gene expression correlated with decreases in the numbers of germ cells at E15.5. After birth, PB-exposed ovaries showed increased proliferation of primary and secondary follicles. We also observed decreases in the numbers of primordial, primary and secondary follicles in adult ovaries from mice that were exposed to PB in utero. Finally, epigenetic alterations such as decreased H3K4me3 and increased H4 acetylation levels were also detected in somatic cells surrounding fully grown oocytes. Conclusion Our data suggest that inhibition of histone deacetylase by PB during a critical developmental window affects reprogramming and germ cell specification via alteration of epigenetic marks.

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Understanding the Role of Trichoderma reesei Vib1 in Gene Expression during Cellulose Degradation

Journal of Fungi ◽

10.3390/jof7080613 ◽

2021 ◽

Vol 7 (8) ◽

pp. 613

Author(s):

Xiuzhen Chen ◽

Bingran Song ◽

Minglu Liu ◽

Lina Qin ◽

Zhiyang Dong

Keyword(s):

Gene Expression ◽

Transcription Factor ◽

Trichoderma Reesei ◽

Cellulose Degradation ◽

Strain Improvement ◽

Cellulase Production ◽

Oxidoreductase Activity ◽

Expression Of Genes ◽

Genes Encoding ◽

Almost All

Vib1, a member of the Ndt80/PhoG-like transcription factor family, has been shown to be essential for cellulase production of Trichoderma reesei. Here, we combined transcriptomic and genetic analyses to gain mechanistic insights into the roles of Vib1 during cellulose degradation. Our transcriptome analysis showed that the vib1 deletion caused 586 genes with decreased expression and 431 genes with increased expression on cellulose. The downregulated genes were enriched for Gene Ontology terms associated with carbohydrate metabolism, transmembrane transport, oxidoreductase activity, and transcription factor activity. Of the 258 genes induced by cellulose, 229 showed no or decreased expression in Δvib1 on cellulose, including almost all (hemi)cellulase genes, crucial sugar transporter genes (IDs:69957, 3405), and the genes encoding main transcriptional activators Xyr1 and Ace3. Additionally, Vib1 also regulated the expression of genes involved in secondary metabolism. Further comparison of the transcriptomes of Δvib1 and Δxyr1 in cellulose revealed that the genes regulated by Vib1 had much overlap with Xyr1 targets especially for the gene set induced by cellulose, presumably whose expression requires the cooperativity between Vib1 and Xyr1. Genetic evidence indicated that Vib1 regulates cellulase gene expression partially via Xyr1. Our results will provide new clues for strain improvement.

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MOTHER-OF-FT-AND-TFL1 represses seed germination under far-red light by modulating phytohormone responses in Arabidopsis thaliana

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1806460115 ◽

2018 ◽

Vol 115 (33) ◽

pp. 8442-8447 ◽

Cited By ~ 20

Author(s):

Fabián E. Vaistij ◽

Thiago Barros-Galvão ◽

Adama F. Cole ◽

Alison D. Gilday ◽

Zhesi He ◽

...

Keyword(s):

Gene Expression ◽

Transcription Factor ◽

Seed Germination ◽

Signaling Pathways ◽

Red Light ◽

Dependent Manner ◽

Light Conditions ◽

Ga Signaling ◽

Expression Of Genes ◽

Genes Encoding

Seed germination in many plant species is triggered by sunlight, which is rich in the red (R) wavelength and repressed by under-the-canopy light rich in far red (FR). R:FR ratios are sensed by phytochromes to regulate levels of gibberellins (GAs) and abscisic acid (ABA), which induce and inhibit germination respectively. In this study we have discovered that, under FR light conditions, germination is repressed by MOTHER-OF-FT-AND-TFL1 (MFT) through the regulation of the ABA and GA signaling pathways. We also show that MFT gene expression is tightly regulated by light quality. Previous work has shown that under FR light conditions the transcription factor PHYOCHROME-INTERACTING-FACTOR1 (PIF1) accumulates and promotes expression of SOMNUS (SOM) that, in turn, leads to increased ABA and decreased GA levels. PIF1 also promotes expression of genes encoding ABA-INSENSITIVE5 (ABI5) and DELLA growth-repressor proteins, which act in the ABA and GA signaling pathways, respectively. Here we show that MFT gene expression is promoted by FR light through the PIF1/SOM/ABI5/DELLA pathway and is repressed by R light via the transcription factor SPATULA (SPT). Consistent with this, we also show that SPT gene expression is repressed under FR light in a PIF1-dependent manner. Furthermore, transcriptomic analyses presented in this study indicate that MFT exerts its function by promoting expression of known ABA-induced genes and repressing cell wall expansion-related genes.

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Genome-Wide STAT3 Binding Analysis after Histone Deacetylase Inhibition Reveals Novel Target Genes in Dendritic Cells

Journal of Innate Immunity ◽

10.1159/000450681 ◽

2016 ◽

Vol 9 (2) ◽

pp. 126-144 ◽

Cited By ~ 6

Author(s):

Yaping Sun ◽

Matthew Iyer ◽

Richard McEachin ◽

Meng Zhao ◽

Yi-Mi Wu ◽

...

Keyword(s):

Gene Expression ◽

Dendritic Cells ◽

Histone Deacetylase ◽

Antigen Processing ◽

Target Genes ◽

Hdac Inhibition ◽

Histone Deacetylase Inhibition ◽

Immune Effector ◽

Chip Sequencing ◽

Genome Wide

STAT3 is a master transcriptional regulator that plays an important role in the induction of both immune activation and immune tolerance in dendritic cells (DCs). The transcriptional targets of STAT3 in promoting DC activation are becoming increasingly understood; however, the mechanisms underpinning its role in causing DC suppression remain largely unknown. To determine the functional gene targets of STAT3, we compared the genome-wide binding of STAT3 using ChIP sequencing coupled with gene expression microarrays to determine STAT3-dependent gene regulation in DCs after histone deacetylase (HDAC) inhibition. HDAC inhibition boosted the ability of STAT3 to bind to distinct DNA targets and regulate gene expression. Among the top 500 STAT3 binding sites, the frequency of canonical motifs was significantly higher than that of noncanonical motifs. Functional analysis revealed that after treatment with an HDAC inhibitor, the upregulated STAT3 target genes were those that were primarily the negative regulators of proinflammatory cytokines and those in the IL-10 signaling pathway. The downregulated STAT3-dependent targets were those involved in immune effector processes and antigen processing/presentation. The expression and functional relevance of these genes were validated. Specifically, functional studies confirmed that the upregulation of IL-10Ra by STAT3 contributed to the suppressive function of DCs following HDAC inhibition.

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Repression of ESR1 through Actions of Estrogen Receptor Alpha and Sin3A at the Proximal Promoter

Molecular and Cellular Biology ◽

10.1128/mcb.00383-09 ◽

2009 ◽

Vol 29 (18) ◽

pp. 4949-4958 ◽

Cited By ~ 47

Author(s):

Stephanie J. Ellison-Zelski ◽

Natalia M. Solodin ◽

Elaine T. Alarid

Keyword(s):

Gene Expression ◽

Estrogen Receptor ◽

Transcription Factor ◽

Rna Polymerase Ii ◽

Transcriptional Repression ◽

Estrogen Receptor Alpha ◽

Proximal Promoter ◽

Receptor Alpha ◽

Expression Of Genes ◽

Activation Of Transcription

ABSTRACT Gene expression results from the coordinated actions of transcription factor proteins and coregulators. Estrogen receptor alpha (ERα) is a ligand-activated transcription factor that can both activate and repress the expression of genes. Activation of transcription by estrogen-bound ERα has been studied in detail, as has antagonist-induced repression, such as that which occurs by tamoxifen. How estrogen-bound ERα represses gene transcription remains unclear. In this report, we identify a new mechanism of estrogen-induced transcriptional repression by using the ERα gene, ESR1. Upon estrogen treatment, ERα is recruited to two sites on ESR1, one distal (ENH1) and the other at the proximal (A) promoter. Coactivator proteins, namely, p300 and AIB1, are found at both ERα-binding sites. However, recruitment of the Sin3A repressor, loss of RNA polymerase II, and changes in histone modifications occur only at the A promoter. Reduction of Sin3A expression by RNA interference specifically inhibits estrogen-induced repression of ESR1. Furthermore, an estrogen-responsive interaction between Sin3A and ERα is identified. These data support a model of repression wherein actions of ERα and Sin3A at the proximal promoter can overcome activating signals at distal or proximal sites and ultimately decrease gene expression.

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Single Cell Transcriptomic Analysis of Spinal Dmrt3 Neurons in Zebrafish and Mouse Identifies Distinct Subtypes and Reveal Novel Subpopulations Within the dI6 Domain

Frontiers in Cellular Neuroscience ◽

10.3389/fncel.2021.781197 ◽

2021 ◽

Vol 15 ◽

Author(s):

Ana Belén Iglesias González ◽

Jon E. T. Jakobsson ◽

Jennifer Vieillard ◽

Malin C. Lagerström ◽

Klas Kullander ◽

...

Keyword(s):

Gene Expression ◽

Transcription Factor ◽

Transcription Factors ◽

Axon Guidance ◽

Single Cell ◽

Cellular Activity ◽

Electrophysiological Properties ◽

Related Transcription Factor ◽

Unique Markers ◽

Molecular Code

The spinal locomotor network is frequently used for studies into how neuronal circuits are formed and how cellular activity shape behavioral patterns. A population of dI6 interneurons, marked by the Doublesex and mab-3 related transcription factor 3 (Dmrt3), has been shown to participate in the coordination of locomotion and gaits in horses, mice and zebrafish. Analyses of Dmrt3 neurons based on morphology, functionality and the expression of transcription factors have identified different subtypes. Here we analyzed the transcriptomes of individual cells belonging to the Dmrt3 lineage from zebrafish and mice to unravel the molecular code that underlies their subfunctionalization. Indeed, clustering of Dmrt3 neurons based on their gene expression verified known subtypes and revealed novel populations expressing unique markers. Differences in birth order, differential expression of axon guidance genes, neurotransmitters, and their receptors, as well as genes affecting electrophysiological properties, were identified as factors likely underlying diversity. In addition, the comparison between fish and mice populations offers insights into the evolutionary driven subspecialization concomitant with the emergence of limbed locomotion.

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Effect of Environmental pH on Morphological Development of Candida albicans Is Mediated via the PacC-Related Transcription Factor Encoded by PRR2

Journal of Bacteriology ◽

10.1128/jb.181.24.7524-7530.1999 ◽

1999 ◽

Vol 181 (24) ◽

pp. 7524-7530 ◽

Cited By ~ 130

Author(s):

Ana M. Ramon ◽

Amalia Porta ◽

William A. Fonzi

Keyword(s):

Gene Expression ◽

Transcription Factor ◽

Candida Albicans ◽

Feedback Loop ◽

Response Regulator ◽

Morphological Development ◽

Alkaline Ph ◽

Ph Response ◽

Related Transcription Factor ◽

Ph Dependent

ABSTRACT The ability to respond to ambient pH is critical to the growth and virulence of the fungal pathogen Candida albicans. This response entails the differential expression of several genes affecting morphogenesis. To investigate the mechanism of pH-dependent gene expression, the C. albicans homolog of pacC, designated PRR2 (for pH response regulator), was identified and cloned. pacC encodes a zinc finger-containing transcription factor that mediates pH-dependent gene expression inAspergillus nidulans. Mutants lacking PRR2 can no longer induce the expression of alkaline-expressed genes or repress acid-expressed genes at alkaline pH. Although the mutation did not affect growth of the cells at acid or alkaline pH, the mutants exhibited medium-conditional defects in filamentation. PRR2was itself expressed in a pH-conditional manner, and its induction at alkaline pH was controlled by PRR1. PRR1 is homologous to palF, a regulator of pacC. Thus,PRR2 expression is controlled by a pH-dependent feedback loop. The results demonstrate that the pH response pathway ofAspergillus is conserved and that this pathway has been adapted to control dimorphism in C. albicans.

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Expression of the apoptosis-releated genes in patients with newly diagnosed chronic lymphocytic leukemia in clinical data context

Russian Journal of Biotherapy ◽

10.17650/1726-9784-2018-17-2-41-46 ◽

2018 ◽

Vol 17 (2) ◽

pp. 41-46 ◽

Cited By ~ 1

Author(s):

S. G. Zakharov ◽

A. K. Golenkov ◽

A. V. Misyurin ◽

E. V. Kataeva ◽

A. A. Rudakova ◽

...

Keyword(s):

Gene Expression ◽

Clinical Manifestations ◽

Multivariate Regression Analysis ◽

Lymphocytic Leukemia ◽

Newly Diagnosed ◽

Expression Of Genes ◽

Gene Level ◽

Genes Encoding ◽

Group Ii ◽

High Level

Introduction.The given data of fundamental studies of apoptosis processes in B-cell lymphocytic leukemia (B-CLL) testifies about the complexity and variety of mechanisms affecting the kinetics of normal cells and tumor lymphocytes in this disease. It is important to study the severity of clinical manifestations of the disease depending on the expression of the genes that modulate apoptosis.The purposeof the study is to compare the activity of genes encoding apoptosis modulators, the cell cycle and cancer-testicular PRAME protein with clinical manifestations of the disease in primary patients with B-CLL.Materials and methods.The level of expression of the proapoptotic genes FAS, TRAIL, TNFR2, DR4/5 and DR3, as well as the HSP27, XIAP genes, blocking apoptosis was determined in 23 patients with newly diagnosed chronic B-CLL. In addition, expression of genes TP53 and P21 and cancer-testis gene PRAME are tested.Results.According to the multivariate regression analysis, the FAS gene expression in the onset of the disease had the greatest impact on the clinical characteristics of the disease. In this connection, the patients were divided into groups with normal (group) and low gene level (group II). A low level of FAS expression (Me 387 %) was associated with stage II disease (p = 0.03), a large number of lympho cytes (p = 0.001), fewer erythrocytes (p = 0.08), and a lower level of TNFR2 gene expression (p = 0.08), high level of expression of XIAP, HSP27, P21. Overall, the anti-apoptotic potential in Group II patients was higher, which was accompanied by more pronounced clinical manifestations of the disease.Conclusions.The increased anti-apoptotic potential of tumor lymphocytes in newly diagnosed B-CLL is accompanied by a larger tumor mass and greater clinical and hematological manifestation of the disease.

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Abstract 191: Transcriptional Regulation of Renin by Nuclear Receptors Co-regulated With Renin

Hypertension ◽

10.1161/hyp.62.suppl_1.a191 ◽

2013 ◽

Vol 62 (suppl_1) ◽

Author(s):

Ko-Ting Lu ◽

Eric T Weatherford ◽

Pimonrat Ketsawatsomkron ◽

Justin L Grobe ◽

Curt D Sigmund

Keyword(s):

Gene Expression ◽

Nuclear Receptors ◽

Estrogen Receptor Alpha ◽

Hormone Receptors ◽

Cell Types ◽

Negative Control ◽

Sirna Duplex ◽

Expression Of Genes ◽

Renin Gene ◽

Genes Encoding

Expression of the renin gene is required to maintain normal morphological and physiological identity of renal juxtaglomerular (JG) cells, yet the mechanisms regulating renin gene transcription remain elusive. We re-examined data from Brunskill et. al (JASN 22:2213, 2011), investigating genome-wide gene expression in JG and other renal cell types. Based on our previous data implicating nuclear receptors (RAR, RXR, VDR, PPARG, Nr2f2 and Nr2f6) in the regulation of mouse and human renin gene expression, we focused our analysis on the expression of genes encoding the 48 nuclear hormone receptors and their co-regulation with renin. Several nuclear receptors have an expression pattern emulating that of renin, that is, they were similarly enriched in JG cells but not in other cell types. These include Esr1, Nr1h4, Ppara, VDR, Nr1i2, Ppard, Hnf4g, Nr1h3, Thrb, Hnf4a, Esrrg, Nr4a3, Nr3c2, and Ar. We tested the hypothesis that a nuclear receptor that is co-regulated with renin may participate in renin gene regulation. To accomplish this, endogenous renin expression was evaluated in renin-expressing As4.1 cells after siRNA-mediated knock down of selected nuclear receptors. Each experiment included a negative control siRNA duplex (NC) that does not target any known genes. By way of example, siRNA-mediated inhibition of estrogen receptor alpha (Esr1) by 70-80% resulted in a 2-fold decrease in renin mRNA (fold change ± SEM: siEsr1: 0.4±0.2, p<0.001 vs NC). Similar results were obtained with a different siRNA targeting Esr1. Interestingly, loss of Esr1 also caused up-regulation of vitamin D receptor (VDR, 2.8±0.7 fold, p<0.001 vs NC) and Nr2f6 (2.0±0.2 fold, p<0.05 vs NC), both of which are known to be negative regulators of renin. Similarly, both renin (0.1±0.02, p<0.001 vs untreated) and Esr1 (0.3±0.1, p<0.05 vs untreated) mRNA were reduced in the kidney from mice treated with deoxycorticosterone acetate (50mg) and receiving 0.15 M NaCl in drinking water for 21 days (DOCA-salt). These data suggest Esr1 may regulate renin expression. Studies are in progress to assess if Esr1 stimulates renin expression on its own or acts by affecting the level of other nuclear receptors; and to determine if other co-regulated nuclear receptors also regulate expression of the renin gene.

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