scholarly journals An enhancer screen identifies new suppressors of small-RNA-mediated epigenetic gene silencing

PLoS Genetics ◽  
2021 ◽  
Vol 17 (6) ◽  
pp. e1009645
Author(s):  
Yukiko Shimada ◽  
Sarah H. Carl ◽  
Merle Skribbe ◽  
Valentin Flury ◽  
Tahsin Kuzdere ◽  
...  
Keyword(s):  
Gene Silencing ◽  
Small Rna ◽  
De Novo ◽  
Single Amino Acid ◽  
Small Interfering Rnas ◽  
Nascent Transcript ◽  
Protein Coding ◽  
Heterochromatin Formation ◽  
Transcript Processing ◽  
Epigenetic Gene Silencing

Small non-protein coding RNAs are involved in pathways that control the genome at the level of chromatin. In Schizosaccharomyces pombe, small interfering RNAs (siRNAs) are required for the faithful propagation of heterochromatin that is found at peri-centromeric repeats. In contrast to repetitive DNA, protein-coding genes are refractory to siRNA-mediated heterochromatin formation, unless siRNAs are expressed in mutant cells. Here we report the identification of 20 novel mutant alleles that enable de novo formation of heterochromatin at a euchromatic protein-coding gene by using trans-acting siRNAs as triggers. For example, a single amino acid substitution in the pre-mRNA cleavage factor Yth1 enables siRNAs to trigger silent chromatin formation with unparalleled efficiency. Our results are consistent with a kinetic nascent transcript processing model for the inhibition of small-RNA-directed de novo formation of heterochromatin and lay a foundation for further mechanistic dissection of cellular activities that counteract epigenetic gene silencing.

Small RNAs in Plant Immunity and Virulence of Filamentous Pathogens

2021 ◽  
Vol 59 (1) ◽  
Author(s):  
Yongli Qiao ◽  
Rui Xia ◽  
Jixian Zhai ◽  
Yingnan Hou ◽  
Li Feng ◽  
...  
Keyword(s):  
Gene Silencing ◽  
Small Rna ◽  
Small Rnas ◽  
Plant Immunity ◽  
Receptor Gene ◽  
Current Status ◽  
Annual Review ◽  
Publication Date ◽  
Small Interfering Rnas ◽  
Host Pathogen

Gene silencing guided by small RNAs governs a broad range of cellular processes in eukaryotes. Small RNAs are important components of plant immunity because they contribute to pathogen-triggered transcription reprogramming and directly target pathogen RNAs. Recent research suggests that silencing of pathogen genes by plant small RNAs occurs not only during viral infection but also in nonviral pathogens through a process termed host-induced gene silencing, which involves trans-species small RNA trafficking. Similarly, small RNAs are also produced by eukaryotic pathogens and regulate virulence. This review summarizes the small RNA pathways in both plants and filamentous pathogens, including fungi and oomycetes, and discusses their role in host–pathogen interactions. We highlight secondary small interfering RNAs of plants as regulators of immune receptor gene expression and executors of host-induced gene silencing in invading pathogens. The current status and prospects of small RNAs trafficking at the host–pathogen interface are discussed. Expected final online publication date for the Annual Review of Phytopathology, Volume 59 is August 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

scholarly journals Induction of H3K9me3 and DNA methylation by tethered heterochromatin factors in Neurospora crassa

2017 ◽  
Vol 114 (45) ◽  
pp. E9598-E9607 ◽  
Author(s):  
Jordan D. Gessaman ◽  
Eric U. Selker
Keyword(s):  
Dna Methylation ◽  
Gene Silencing ◽  
Neurospora Crassa ◽  
Dna Methyltransferase ◽  
Catalytic Domain ◽  
De Novo ◽  
Histone Deacetylation ◽  
Heterochromatin Formation ◽  
Histone Deacetylase 1

Functionally different chromatin domains display distinct chemical marks. Constitutive heterochromatin is commonly associated with trimethylation of lysine 9 on histone H3 (H3K9me3), hypoacetylated histones, and DNA methylation, but the contributions of and interplay among these features are not fully understood. To dissect the establishment of heterochromatin, we investigated the relationships among these features using an in vivo tethering system in Neurospora crassa. Artificial recruitment of the H3K9 methyltransferase DIM-5 (defective in methylation-5) induced H3K9me3 and DNA methylation at a normally active, euchromatic locus but did not bypass the requirement of DIM-7, previously implicated in the localization of DIM-5, indicating additional DIM-7 functionality. Tethered heterochromatin protein 1 (HP1) induced H3K9me3, DNA methylation, and gene silencing. The induced heterochromatin required histone deacetylase 1 (HDA-1), with an intact catalytic domain, but HDA-1 was not essential for de novo heterochromatin formation at native heterochromatic regions. Silencing did not require H3K9me3 or DNA methylation. However, DNA methylation contributed to establishment of H3K9me3 induced by tethered HP1. Our analyses also revealed evidence of regulatory mechanisms, dependent on HDA-1 and DIM-5, to control the localization and catalytic activity of the DNA methyltransferase DIM-2. Our study clarifies the interrelationships among canonical aspects of heterochromatin and supports a central role of HDA-1–mediated histone deacetylation in heterochromatin spreading and gene silencing.

scholarly journals The Paf1 complex represses small-RNA-mediated epigenetic gene silencing

Nature ◽  
2015 ◽  
Vol 520 (7546) ◽  
pp. 248-252 ◽  
Author(s):  
Katarzyna Maria Kowalik ◽  
Yukiko Shimada ◽  
Valentin Flury ◽  
Michael Beda Stadler ◽  
Julia Batki ◽  
...  
Keyword(s):  
Gene Silencing ◽  
Small Rna ◽  
Epigenetic Gene Silencing ◽  
Paf1 Complex

scholarly journals The Paf1 complex broadly impacts the transcriptome ofSaccharomyces cerevisiae

2019 ◽  
Author(s):  
Mitchell A. Ellison ◽  
Alex R. Lederer ◽  
Marcie H. Warner ◽  
Travis Mavrich ◽  
Elizabeth A. Raupach ◽  
...  
Keyword(s):  
Gene Expression ◽  
De Novo ◽  
Differential Expression Analysis ◽  
Chromatin Modification ◽  
Antisense Transcription ◽  
Yeast Genome ◽  
Mrna Levels ◽  
Nascent Transcript ◽  
Protein Coding ◽  
Multiple Loci

ABSTRACTThe Polymerase Associated Factor 1 complex (Paf1C) is a multifunctional regulator of eukaryotic gene expression important for the coordination of transcription with chromatin modification and post-transcriptional processes. In this study, we investigated the extent to which the functions of Paf1C combine to regulate theSaccharomyces cerevisiaetranscriptome. While previous studies focused on the roles of Paf1C in controlling mRNA levels, here we took advantage of a genetic background that enriches for unstable transcripts and demonstrate that deletion ofPAF1affects all classes of Pol II transcripts including multiple classes of noncoding RNAs. By conducting ade novodifferential expression analysis independent of gene annotations, we found that Paf1 positively and negatively regulates antisense transcription at multiple loci. Comparisons with nascent transcript data revealed that many, but not all, changes in RNA levels detected by our analysis are due to changes in transcription instead of post-transcriptional events. To investigate the mechanisms by which Paf1 regulates protein-coding genes, we focused on genes involved in iron and phosphate homeostasis, which were differentially affected byPAF1deletion. Our results indicate that Paf1 stimulates phosphate gene expression through a mechanism that is independent of any individual Paf1C-dependent histone modification. In contrast, the inhibition of iron gene expression by Paf1 correlates with a defect in H3 K36 tri-methylation. Finally, we showed that one iron regulon gene,FET4, is coordinately controlled by Paf1 and transcription of upstream noncoding DNA. Together these data identify roles for Paf1C in controlling both coding and noncoding regions of the yeast genome.

scholarly journals RNA Interference: Biology, Mechanism, and Applications

2003 ◽  
Vol 67 (4) ◽  
pp. 657-685 ◽  
Author(s):  
Neema Agrawal ◽  
P. V. N. Dasaradhi ◽  
Asif Mohmmed ◽  
Pawan Malhotra ◽  
Raj K. Bhatnagar ◽  
...  
Keyword(s):  
Gene Silencing ◽  
Defense Mechanisms ◽  
Specific Gene ◽  
Small Interfering Rnas ◽  
Allelic Series ◽  
Rnase Iii ◽  
Heterochromatin Formation ◽  
Regulatory Processes ◽  
Micro Rnas ◽  
And Function

SUMMARY Double-stranded RNA-mediated interference (RNAi) is a simple and rapid method of silencing gene expression in a range of organisms. The silencing of a gene is a consequence of degradation of RNA into short RNAs that activate ribonucleases to target homologous mRNA. The resulting phenotypes either are identical to those of genetic null mutants or resemble an allelic series of mutants. Specific gene silencing has been shown to be related to two ancient processes, cosuppression in plants and quelling in fungi, and has also been associated with regulatory processes such as transposon silencing, antiviral defense mechanisms, gene regulation, and chromosomal modification. Extensive genetic and biochemical analysis revealed a two-step mechanism of RNAi-induced gene silencing. The first step involves degradation of dsRNA into small interfering RNAs (siRNAs), 21 to 25 nucleotides long, by an RNase III-like activity. In the second step, the siRNAs join an RNase complex, RISC (RNA-induced silencing complex), which acts on the cognate mRNA and degrades it. Several key components such as Dicer, RNA-dependent RNA polymerase, helicases, and dsRNA endonucleases have been identified in different organisms for their roles in RNAi. Some of these components also control the development of many organisms by processing many noncoding RNAs, called micro-RNAs. The biogenesis and function of micro-RNAs resemble RNAi activities to a large extent. Recent studies indicate that in the context of RNAi, the genome also undergoes alterations in the form of DNA methylation, heterochromatin formation, and programmed DNA elimination. As a result of these changes, the silencing effect of gene functions is exercised as tightly as possible. Because of its exquisite specificity and efficiency, RNAi is being considered as an important tool not only for functional genomics, but also for gene-specific therapeutic activities that target the mRNAs of disease-related genes.

The role of non-coding RNAs

2019 ◽  
pp. 69-79
Author(s):  
John C. Lucchesi
Keyword(s):  
Target Genes ◽  
Centromeric Heterochromatin ◽  
Small Interfering Rnas ◽  
Protein Coding ◽  
Heterochromatin Formation ◽  
Short Rnas ◽  
Micro Rnas ◽  
Rrna Maturation ◽  
Non Coding Rnas

Most of the genome is transcribed into non-coding transcripts that far exceed in number the transcripts of protein-coding genes. These RNAs are subdivided into different classes. Long non-coding RNAs (lncRNAs) are at least 200 nucleotides in length and are transcribed from promoter, coding, intergenic or enhancer regions (eRNAs). These RNAs repress or enhance the transcription of target genes by facilitating the interaction between promoters and enhancers or by interacting with transcription factors and targeting histone-modifying enzymes. Short non-coding RNAs include a diverse group of functional types: miRNAs (micro RNAs) and siRNAs (small interfering RNAs) are negative regulators of gene expression; piRNAs (Piwi-interacting RNAs) suppress the action of transposable elements in the germline; snRNAs (small nuclear RNAs) are involved in mRNA splicing and rRNA maturation; tRNA-derived non-coding RNAs are involved in the cellular reaction to stress and in the repression of gene function. Additional short RNAs are rasiRNAs (repeat-associated small interfering RNAs) that appear to be involved in centromeric heterochromatin formation.

Computational study for suppression of CD25/IL-2 interaction

2020 ◽  
Vol 0 (0) ◽  
Author(s):  
Moein Dehbashi ◽  
Zohreh Hojati ◽  
Majid Motovali-bashi ◽  
Mazdak Ganjalikhani-Hakemi ◽  
Akihiro Shimosaka ◽  
...  
Keyword(s):  
Small Molecules ◽  
Cancer Progression ◽  
Immune Escape ◽  
De Novo ◽  
Computational Study ◽  
Treg Cells ◽  
Homology Search ◽  
Small Interfering Rnas

AbstractCancer recurrence presents a huge challenge in cancer patient management. Immune escape is a key mechanism of cancer progression and metastatic dissemination. CD25 is expressed in regulatory T (Treg) cells including tumor-infiltrating Treg cells (TI-Tregs). These cells specially activate and reinforce immune escape mechanism of cancers. The suppression of CD25/IL-2 interaction would be useful against Treg cells activation and ultimately immune escape of cancer. Here, software, web servers and databases were used, at which in silico designed small interfering RNAs (siRNAs), de novo designed peptides and virtual screened small molecules against CD25 were introduced for the prospect of eliminating cancer immune escape and obtaining successful treatment. We obtained siRNAs with low off-target effects. Further, small molecules based on the binding homology search in ligand and receptor similarity were introduced. Finally, the critical amino acids on CD25 were targeted by a de novo designed peptide with disulfide bond. Hence we introduced computational-based antagonists to lay a foundation for further in vitro and in vivo studies.

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