scholarly journals Transcriptional adaptation in Caenorhabditis elegans

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Vahan Serobyan ◽  
Zacharias Kontarakis ◽  
Mohamed A El-Brolosy ◽  
Jordan M Welker ◽  
Oleg Tolstenkov ◽  
...  
Keyword(s):  
Small Rna ◽  
Protein Function ◽  
Molecular Mechanisms ◽  
Molecular Level ◽  
Mouse Cell ◽  
C Elegans ◽  
Argonaute Proteins ◽  
Transcriptional Modulation ◽  
Transcriptional Adaptation ◽  
Rna Maturation

Transcriptional adaptation is a recently described phenomenon by which a mutation in one gene leads to the transcriptional modulation of related genes, termed adapting genes. At the molecular level, it has been proposed that the mutant mRNA, rather than the loss of protein function, activates this response. While several examples of transcriptional adaptation have been reported in zebrafish embryos and in mouse cell lines, it is not known whether this phenomenon is observed across metazoans. Here we report transcriptional adaptation in C. elegans, and find that this process requires factors involved in mutant mRNA decay, as in zebrafish and mouse. We further uncover a requirement for Argonaute proteins and Dicer, factors involved in small RNA maturation and transport into the nucleus. Altogether, these results provide evidence for transcriptional adaptation in C. elegans, a powerful model to further investigate underlying molecular mechanisms.

scholarly journals C. elegans PVD Neurons: A Platform for Functionally Validating and Characterizing Neuropsychiatric Risk Genes

2016 ◽  
Author(s):  
Cristina Aguirre-Chen ◽  
Nuri Kim ◽  
Olivia Mendivil Ramos ◽  
Melissa Kramer ◽  
W. Richard McCombie ◽  
...  
Keyword(s):  
Protein Function ◽  
Molecular Mechanisms ◽  
Neuronal Development ◽  
De Novo ◽  
Genetic Interaction ◽  
Cost Effective ◽  
Chromatin Remodelers ◽  
C Elegans ◽  
Effective Manner

AbstractOne of the primary challenges in the field of psychiatric genetics is the lack of an in vivo model system in which to functionally validate candidate neuropsychiatric risk genes (NRGs) in a rapid and cost-effective manner1−3. To overcome this obstacle, we performed a candidate-based RNAi screen in which C. elegans orthologs of human NRGs were assayed for dendritic arborization and cell specification defects using C. elegans PVD neurons. Of 66 NRGs, identified via exome sequencing of autism (ASD)4 or schizophrenia (SCZ)5−9 probands and whose mutations are de novo and predicted to result in a complete or partial loss of protein function, the C. elegans orthologs of 7 NRGs were found to be required for proper neuronal development and represent a variety of functional classes, including transcriptional regulators and chromatin remodelers, molecular chaperones, and cytoskeleton-related proteins. Notably, the positive hit rate, when selectively assaying C. elegans orthologs of ASD and SCZ NRGs, is enriched >14-fold as compared to unbiased RNAi screening10. Furthermore, we find that RNAi phenotypes associated with the depletion of NRG orthologs is recapitulated in genetic mutant animals, and, via genetic interaction studies, we show that the NRG ortholog of ANK2, unc-44, is required for SAX-7/MNR-1/DMA-1 signaling. Collectively, our studies demonstrate that C. elegans PVD neurons are a tractable model in which to discover and dissect the fundamental molecular mechanisms underlying neuropsychiatric disease pathogenesis.

scholarly journals Regulation of Autophagy in Aging and Disease

2020 ◽  
Vol 4 (Supplement_1) ◽  
pp. 743-744
Author(s):  
Malene Hansen
Keyword(s):  
Molecular Mechanisms ◽  
Molecular Level ◽  
Recycling Process ◽  
Cellular Homeostasis ◽  
C Elegans ◽  
Age Related ◽  
Multiple Levels ◽  
Critical Process

Abstract The cytosolic recycling process of autophagy plays an important role in many age-related diseases and has been directly linked to aging, including in the nematode C. elegans where autophagy appears beneficially induced in many conserved longevity models. As a critical process to ensure cellular homeostasis, autophagy is regulated at multiple levels, yet it remains a challenge in the field to understand how the regulation of autophagy is integrated at the cellular and molecular level to ensure health- and lifespan benefits. I will here discuss our progress on understanding the different molecular mechanisms employed by cells and organisms to regulate autophagy in response to stressors such as aging and disease.

scholarly journals GTSF-1 is required for the formation of a functional RNA-dependent RNA Polymerase complex in C. elegans

2018 ◽  
Author(s):  
Miguel Vasconcelos Almeida ◽  
Sabrina Dietz ◽  
Stefan Redl ◽  
Emil Karaulanov ◽  
Andrea Hildebrandt ◽  
...  
Keyword(s):  
Rna Polymerase ◽  
Gene Silencing ◽  
Small Rna ◽  
Small Rnas ◽  
Zinc Fingers ◽  
Specific Factor ◽  
Rna Dependent Rna Polymerase ◽  
C Elegans ◽  
Argonaute Proteins ◽  
Rna Pathways

AbstractIn every domain of life, Argonaute proteins and their associated small RNAs regulate gene expression. Despite great conservation of Argonaute proteins throughout evolution, many proteins acting in small RNA pathways are not widely conserved. Gametocyte-specific factor 1 (Gtsf1) proteins, characterized by two tandem CHHC zinc fingers and an unstructured, acidic C-terminal tail, are conserved in animals and act in small RNA pathways. In fly and mouse, they are required for fertility and have been shown to interact with Piwi clade Argonautes. We identified T06A10.3 as the Caenorhabditis elegans Gtsf1 homolog and named it gtsf-1. Given its conserved nature and roles in Piwi-mediated gene silencing, we sought out to characterize GTSF-1 in the context of the small RNA pathways of C. elegans. Like its homologs, GTSF-1 is required for normal fertility. Surprisingly, we report that GTSF-1 is not required for Piwi-mediated gene silencing. Instead, gtsf-1 mutants show strong depletion of a class of endogenous small RNAs, known as 26G-RNAs, and fully phenocopy mutants lacking RRF-3, the RNA-dependent RNA Polymerase that synthesizes 26G-RNAs. We show, both in vivo and in vitro, that GTSF-1 specifically and robustly interacts with RRF-3 via its tandem CHHC zinc fingers. Furthermore, we demonstrate that GTSF-1 is required for the assembly of a larger RRF-3 and DCR-1-containing complex, also known as ERIC, thereby allowing for 26G-RNA generation. We propose that GTSF-1 homologs may similarly act to drive the assembly of larger complexes that subsequently act in small RNA production and/or in imposing small RNA-mediated silencing activities.

scholarly journals Transcriptional adaptation: a mechanism underlying genetic robustness

Development ◽  
2020 ◽  
Vol 147 (15) ◽  
pp. dev186452 ◽  
Author(s):  
Tamar E. Sztal ◽  
Didier Y. R. Stainier
Keyword(s):  
Genetic Variation ◽  
Protein Function ◽  
Regulatory Elements ◽  
Mrna Degradation ◽  
Coding Regions ◽  
Genetic Robustness ◽  
Genetic Perturbations ◽  
Transcriptional Modulation ◽  
Transcriptional Adaptation ◽  
Upregulated Genes

ABSTRACTMutations play a crucial role in evolution as they provide the genetic variation that allows evolutionary change. Although some mutations in regulatory elements or coding regions can be beneficial, a large number of them disrupt gene function and reduce fitness. Organisms utilize several mechanisms to compensate for the damaging consequences of genetic perturbations. One such mechanism is the recently identified process of transcriptional adaptation (TA): during this event, mutations that cause mutant mRNA degradation trigger the transcriptional modulation of so-called adapting genes. In some cases, for example when one (or more) of the upregulated genes is functionally redundant with the mutated gene, this process compensates for the loss of the mutated gene's product. Notably, unlike other mechanisms underlying genetic robustness, TA is not triggered by the loss of protein function, an observation that has prompted studies into the machinery of TA and the contexts in which it functions. Here, we review the discovery and current understanding of TA, and discuss how its main features appear to be conserved across species. In light of these findings, we also speculate on the importance of TA in the context of human disease, and provide some recommendations for genome-editing strategies that should be more effective.

scholarly journals Regulation of Autophagy in Aging and Disease

2020 ◽  
Vol 4 (Supplement_1) ◽  
pp. 744-744
Author(s):  
Malene Hansen
Keyword(s):  
Molecular Mechanisms ◽  
Molecular Level ◽  
Recycling Process ◽  
Cellular Homeostasis ◽  
C Elegans ◽  
Age Related ◽  
Multiple Levels ◽  
Critical Process

Abstract The cytosolic recycling process of autophagy plays an important role in many age-related diseases and has been directly linked to aging, including in the nematode C. elegans where autophagy appears beneficially induced in many conserved longevity models. As a critical process to ensure cellular homeostasis, autophagy is regulated at multiple levels, yet it remains a challenge in the field to understand how the regulation of autophagy is integrated at the cellular and molecular level to ensure health- and lifespan benefits. I will here discuss our progress on understanding the different molecular mechanisms employed by cells and organisms to regulate autophagy in response to stressors such as aging and disease.

scholarly journals Two isoforms of the essential C. elegans Argonaute CSR-1 differentially regulate sperm and oocyte fertility through distinct small RNA classes

2020 ◽  
Author(s):  
Amanda G. Charlesworth ◽  
Nicolas J. Lehrbach ◽  
Uri Seroussi ◽  
Mathias S. Renaud ◽  
Ruxandra I. Molnar ◽  
...  
Keyword(s):  
Small Rna ◽  
Regulatory Network ◽  
Small Rnas ◽  
Male Fertility ◽  
Expression Patterns ◽  
C Elegans ◽  
Argonaute Proteins ◽  
Germline Genes ◽  
Somatic Tissues ◽  
Normal Laboratory

SUMMARYThe C. elegans genome encodes nineteen functional Argonaute proteins that utilize 22G-RNAs, 26G-RNAs, miRNAs, or piRNAs to regulate their target transcripts. Only one of these proteins is essential under normal laboratory conditions: CSR-1. While CSR-1 has been studied in various developmental and functional contexts, nearly all studies investigating CSR-1 have overlooked the fact that the csr-1 locus encodes two isoforms. These isoforms differ by an additional 163 amino acids present in the N-terminus of CSR-1a. Using CRISPR-Cas9 genome editing to introduce GFP::3xFLAG epitopes into the long (CSR-1a) and short (CSR-1b) isoforms of CSR-1, we identified differential expression patterns for the two isoforms. CSR-1a is expressed specifically during spermatogenesis and in select somatic tissues, including the intestine. In contrast, CSR-1b, is expressed constitutively in the germline. Essential functions of csr-1 described in the literature coincide with CSR-1b. In contrast, CSR-1a plays tissue specific functions during spermatogenesis, where it integrates into a spermatogenesis sRNA regulatory network including ALG-3, ALG-4, and WAGO-10 that is necessary for male fertility. CSR-1a is also required in the intestine for the silencing of repetitive transgenes. Sequencing of small RNAs associated with each CSR-1 isoform reveals that CSR-1a engages with 22G- and 26G-RNAs, while CSR-1b interacts with only 22G-RNAs to regulate distinct groups of germline genes and regulate both sperm and oocyte-mediated fertility.

scholarly journals Genetic compensation is triggered by mutant mRNA degradation

2018 ◽  
Author(s):  
Mohamed A. El-Brolosy ◽  
Andrea Rossi ◽  
Zacharias Kontarakis ◽  
Carsten Kuenne ◽  
Stefan Günther ◽  
...  
Keyword(s):  
Protein Function ◽  
Mrna Decay ◽  
Degradation Products ◽  
Sequence Similarity ◽  
Mrna Degradation ◽  
Mrna Surveillance ◽  
Transcriptional Modulation ◽  
Transcriptional Adaptation ◽  
Genetic Compensation

Genetic compensation by transcriptional modulation of related gene(s) (also known as transcriptional adaptation) has been reported in numerous systems1–3; however, whether and how such a response can be activated in the absence of protein feedback loops is unknown. Here, we develop and analyze several models of transcriptional adaptation in zebrafish and mouse that we show are not caused by loss of protein function. We find that the increase in transcript levels is due to enhanced transcription, and observe a correlation between the levels of mutant mRNA decay and transcriptional upregulation of related genes. To assess the role of mutant mRNA degradation in triggering transcriptional adaptation, we use genetic and pharmacological approaches and find that mRNA degradation is indeed required for this process. Notably, uncapped RNAs, themselves subjected to rapid degradation, can also induce transcriptional adaptation. Next, we generate alleles that fail to transcribe the mutated gene and find that they do not show transcriptional adaptation, and exhibit more severe phenotypes than those observed in alleles displaying mutant mRNA decay. Transcriptome analysis of these different alleles reveals the upregulation of hundreds of genes with enrichment for those showing sequence similarity with the mutated gene’s mRNA, suggesting a model whereby mRNA degradation products induce the response via sequence similarity. These results expand the role of the mRNA surveillance machinery in buffering against mutations by triggering the transcriptional upregulation of related genes. Besides implications for our understanding of disease-causing mutations, our findings will help design mutant alleles with minimal transcriptional adaptation-derived compensation.

How do histone modifications contribute to transgenerational epigenetic inheritance in C. elegans?

2020 ◽  
Vol 48 (3) ◽  
pp. 1019-1034 ◽  
Author(s):  
Rachel M. Woodhouse ◽  
Alyson Ashe
Keyword(s):  
Histone Modifications ◽  
Molecular Mechanisms ◽  
Epigenetic Inheritance ◽  
Nematode Caenorhabditis Elegans ◽  
Histone Methyltransferases ◽  
Transgenerational Epigenetic Inheritance ◽  
C Elegans ◽  
Recent Developments ◽  
Gene Regulatory

Gene regulatory information can be inherited between generations in a phenomenon termed transgenerational epigenetic inheritance (TEI). While examples of TEI in many animals accumulate, the nematode Caenorhabditis elegans has proven particularly useful in investigating the underlying molecular mechanisms of this phenomenon. In C. elegans and other animals, the modification of histone proteins has emerged as a potential carrier and effector of transgenerational epigenetic information. In this review, we explore the contribution of histone modifications to TEI in C. elegans. We describe the role of repressive histone marks, histone methyltransferases, and associated chromatin factors in heritable gene silencing, and discuss recent developments and unanswered questions in how these factors integrate with other known TEI mechanisms. We also review the transgenerational effects of the manipulation of histone modifications on germline health and longevity.

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