scholarly journals Adar-mediated A-to-I editing is required for establishment of embryonic body axes in zebrafish

2021 ◽  
Author(s):  
Katarzyna Niescierowicz ◽  
Leszek Pryszcz ◽  
Cristina Navarrete ◽  
Eugeniusz Tralle ◽  
Marta Elzbieta Kasprzyk ◽  
...  
Keyword(s):  
Gene Expression ◽  
Rna Editing ◽  
Embryonic Patterning ◽  
Zebrafish Development ◽  
Adenosine Deaminases ◽  
Genome Wide

Adenosine deaminases (ADARs) catalyze the deamination of adenosine to inosine, also known as A-to-I editing, in RNA. Although A-to-I editing occurs widely across animals, and is well studied, new biological roles are still being discovered. Here, we study the role of A-to-I editing in early zebrafish development. We demonstrate that Adar, the zebrafish orthologue of mammalian ADAR1, is essential for establishing the antero-posterior and dorso-ventral axes and patterning. Genome-wide editing discovery revealed pervasive editing in maternal and the earliest zygotic transcripts, the majority of which occurred in the 3-UTR. Interestingly, transcripts implicated in gastrulation as well as dorso-ventral and antero-posterior patterning were found to contain multiple editing sites. Adar knockdown or overexpression affected gene expression and global editing patterns at 12 hpf, but not earlier. Our study established that RNA editing by Adar is necessary for the earliest steps of embryonic patterning along the zebrafish antero-posterior and dorso-ventral axes.

Artificial RNA Editing with ADAR for Gene Therapy

2020 ◽  
Vol 20 (1) ◽  
pp. 44-54 ◽  
Author(s):  
Sonali Bhakta ◽  
Toshifumi Tsukahara
Keyword(s):  
Gene Therapy ◽  
Genetic Code ◽  
Molecular Mechanism ◽  
Rna Editing ◽  
Comparative Studies ◽  
Genetic Diseases ◽  
Adenosine Deaminases ◽  
Family Protein ◽  
Hydrolytic Deamination

Editing mutated genes is a potential way for the treatment of genetic diseases. G-to-A mutations are common in mammals and can be treated by adenosine-to-inosine (A-to-I) editing, a type of substitutional RNA editing. The molecular mechanism of A-to-I editing involves the hydrolytic deamination of adenosine to an inosine base; this reaction is mediated by RNA-specific deaminases, adenosine deaminases acting on RNA (ADARs), family protein. Here, we review recent findings regarding the application of ADARs to restoring the genetic code along with different approaches involved in the process of artificial RNA editing by ADAR. We have also addressed comparative studies of various isoforms of ADARs. Therefore, we will try to provide a detailed overview of the artificial RNA editing and the role of ADAR with a focus on the enzymatic site directed A-to-I editing.

DDR1 methylation is associated with bipolar disorder and the isoform expression and methylation of myelin genes

Epigenomics ◽  
2021 ◽  
Author(s):  
Beatriz Garcia-Ruiz ◽  
Manuel Castro de Moura ◽  
Gerard Muntané ◽  
Lourdes Martorell ◽  
Elena Bosch ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Bipolar Disorder ◽  
Mrna Expression ◽  
Gene Expression Analysis ◽  
Mrna Levels ◽  
Healthy Controls ◽  
Genome Wide ◽  
Isoform Expression

Aim: To investigate DDR1 methylation in the brains of bipolar disorder (BD) patients and its association with DDR1 mRNA levels and comethylation with myelin genes. Materials & methods: Genome-wide profiling of DNA methylation (Infinium MethylationEPIC BeadChip) corrected for glial composition and DDR1 gene expression analysis in the occipital cortices of individuals with BD (n = 15) and healthy controls (n = 15) were conducted. Results: DDR1 5-methylcytosine levels were increased and directly associated with DDR1b mRNA expression in the brains of BD patients. We also observed that DDR1 was comethylated with a group of myelin genes. Conclusion: DDR1 is hypermethylated in BD brain tissue and is associated with isoform expression. Additionally, DDR1 comethylation with myelin genes supports the role of this receptor in myelination.

scholarly journals Epigenetic mechanisms in sexual differentiation of the brain and behaviour

2016 ◽  
Vol 371 (1688) ◽  
pp. 20150114 ◽  
Author(s):  
Nancy G. Forger
Keyword(s):  
Gene Expression ◽  
Sex Differences ◽  
Sexual Differentiation ◽  
Wide Distribution ◽  
Epigenetic Modifications ◽  
Epigenetic Mechanism ◽  
Epigenetic Mechanisms ◽  
Genome Wide ◽  
The Brain

Circumstantial evidence alone argues that the establishment and maintenance of sex differences in the brain depend on epigenetic modifications of chromatin structure. More direct evidence has recently been obtained from two types of studies: those manipulating a particular epigenetic mechanism, and those examining the genome-wide distribution of specific epigenetic marks. The manipulation of histone acetylation or DNA methylation disrupts the development of several neural sex differences in rodents. Taken together, however, the evidence suggests there is unlikely to be a simple formula for masculine or feminine development of the brain and behaviour; instead, underlying epigenetic mechanisms may vary by brain region or even by dependent variable within a region. Whole-genome studies related to sex differences in the brain have only very recently been reported, but suggest that males and females may use different combinations of epigenetic modifications to control gene expression, even in cases where gene expression does not differ between the sexes. Finally, recent findings are discussed that are likely to direct future studies on the role of epigenetic mechanisms in sexual differentiation of the brain and behaviour.

Genome wide quantification of A-to-I RNA editing activity

2019 ◽  
Author(s):  
Shalom Hillel Roth ◽  
Erez Y. Levanon ◽  
Eli Eisenberg
Keyword(s):  
Rna Editing ◽  
Innate Immune ◽  
Rna Modification ◽  
Immune Disorders ◽  
Computational Tool ◽  
Genome Wide ◽  
Editing Activity ◽  
Single Number ◽  
Editing Level

Abstract Adenosine to inosine (A-to-I) RNA editing by the ADAR enzymes is a common RNA modification, preventing false activation of the innate immune system by endogenous dsRNAs. Methods for quantification of ADAR activity are sought after, due to an increasing interest in the role of ADARs in cancer and auto-immune disorders, as well as attempts to harness the ADAR enzymes for RNA engineering. Here we present the Alu Editing Index (AEI), a robust and simple-to-use computational tool devised for this purpose that produces a single number representing the global editing level from BAM files. The AEI tool is available at https://github.com/a2iEditing/RNAEditingIndexer

scholarly journals Listeria monocytogenes σB Modulates PrfA-Mediated Virulence Factor Expression

2009 ◽  
Vol 77 (5) ◽  
pp. 2113-2124 ◽  
Author(s):  
Juliane Ollinger ◽  
Barbara Bowen ◽  
Martin Wiedmann ◽  
Kathryn J. Boor ◽  
Teresa M. Bergholz
Keyword(s):  
Gene Expression ◽  
Listeria Monocytogenes ◽  
Transcriptional Activation ◽  
Virulence Gene ◽  
Transcript Profiling ◽  
Virulence Gene Expression ◽  
Qrt Pcr ◽  
Genome Wide

ABSTRACT Listeria monocytogenes σB and positive regulatory factor A (PrfA) are pleiotropic transcriptional regulators that coregulate a subset of virulence genes. A positive regulatory role for σB in prfA transcription has been well established; therefore, observations of increased virulence gene expression and hemolytic activity in a ΔsigB strain initially appeared paradoxical. To test the hypothesis that L. monocytogenes σB contributes to a regulatory network critical for appropriate repression as well as induction of virulence gene expression, genome-wide transcript profiling and follow-up quantitative reverse transcriptase PCR (qRT-PCR), reporter fusion, and phenotypic experiments were conducted using L. monocytogenes prfA*, prfA* ΔsigB, ΔprfA, and ΔprfA ΔsigB strains. Genome-wide transcript profiling and qRT-PCR showed that in the presence of active PrfA (PrfA*), σB is responsible for reduced expression of the PrfA regulon. σB-dependent modulation of PrfA regulon expression reduced the cytotoxic effects of a PrfA* strain in HepG2 cells, highlighting the functional importance of regulatory interactions between PrfA and σB. The emerging model of the role of σB in regulating overall PrfA activity includes a switch from transcriptional activation at the P2 prfA promoter (e.g., in extracellular bacteria when PrfA activity is low) to posttranscriptional downregulation of PrfA regulon expression (e.g., in intracellular bacteria when PrfA activity is high).

A-To-I RNA Editing By ADAR1 Is Essential For Hematopoiesis

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1199-1199 ◽  
Author(s):  
Brian Liddicoat ◽  
Robert Piskol ◽  
Alistair Chalk ◽  
Miyoko Higuchi ◽  
Peter Seeburg ◽  
...  
Keyword(s):  
Gene Expression ◽  
Rna Editing ◽  
Fetal Liver ◽  
Expression Profiles ◽  
In Utero ◽  
Tamoxifen Treatment ◽  
Rna Seq ◽  
Data Set ◽  
Hematopoietic Stem

Abstract The role of RNA and its regulation is becoming increasingly appreciated as a vital component of hematopoietic development. RNA editing by members of the Adenosine Deaminase Acting on RNA (ADAR) gene family is a form of post-transcriptional modification which converts genomically encoded adenosine to inosine (A-to-I) in double-stranded RNA. A-to-I editing by ADAR directly converts the sequence of the RNA substrate and can alter the structure, function, processing, and localization of the targeted RNA. ADAR1 is ubiquitously expressed and we have previously described essential roles in the development of hematopoietic and hepatic organs. Germline ablation of murine ADAR1 results in a significant upregulation of interferon (IFN) stimulated genes and embryonic death between E11.5 and E12.5 associated with fetal liver disintegration and failed hemopoiesis. To determine the biological importance of A-to-I editing by ADAR1, we generated an editing dead knock-in allele of ADAR1 (ADAR1E861A). Mice homozygous for the ADAR1E861A allele died in utero at ∼E13.5. The fetal liver (FL) was small and had significantly lower cellularity than in controls. Analysis of hemopoiesis demonstrated increased apoptosis and a loss of hematopoietic stem cells (HSC) and all mature lineages. Most notably erythropoiesis was severely impaired with ∼7-fold reduction across all erythrocyte progenitor populations compared to controls. These data are consistent with our previous findings that ADAR1 is essential for erythropoiesis (unpublished data) and suggest that the ADAR1E861A allele phenocopies the null allele in utero. To assess the requirement of A-to-I editing in adult hematopoiesis, we generated mice where we could somatically delete the wild-type ADAR1 allele and leave only ADAR1E861A expressed in HSCs (hScl-CreERAdar1fl/E861A). In comparison to hScl-CreERAdar1fl/+ controls, hScl-CreERAdar1fl/E861A mice were anemic and had severe leukopenia 20 days post tamoxifen treatment. Investigation of marrow hemopoiesis revealed a significant loss of all cells committed to the erythroid lineage in hScl-CreERAdar1fl/E861A mice, despite having elevated phenotypic HSCs. Upon withdrawal of tamoxifen diet, all blood parameters were restored to control levels within 12 weeks owing to strong selection against cells expressing only the ADAR1E861A allele. To understand the mechanism through which ADAR1 mediated A-to-I editing regulates hematopoiesis, RNA-seq was performed. Gene expression profiles showed that a loss of ADAR1 mediated A-to-I editing resulted in a significant upregulation of IFN signatures, consistent with the gene expression changes in ADAR1 null mice. To define substrates of ADAR1 we assessed A-to-I mismatches in the RNA-seq data sets. 3,560 previously known and 353 novel A-to-I editing sites were identified in our data set. However, no single editing substrate discovered could account for the IFN signature observed or the lethality of ADAR1E861A/E861A mice. These results demonstrate that ADAR1 mediated A-to-I editing is essential for the maintenance of both fetal and adult hemopoiesis in a cell-autonomous manner and a key suppressor of the IFN response in hematopoiesis. Furthermore the ADAR1E861A allele demonstrates the essential role of ADAR1 in vivo is A-to-I editing. Disclosures: Hartner: TaconicArtemis: Employment.

scholarly journals The genome-wide role of HSF-1 in the regulation of gene expression in Caenorhabditis elegans

BMC Genomics ◽  
2016 ◽  
Vol 17 (1) ◽  
Author(s):  
Jessica Brunquell ◽  
Stephanie Morris ◽  
Yin Lu ◽  
Feng Cheng ◽  
Sandy D. Westerheide
Keyword(s):  
Gene Expression ◽  
Caenorhabditis Elegans ◽  
Regulation Of Gene Expression ◽  
Genome Wide

scholarly journals Correlation between Bacillus subtilis scoC Phenotype and Gene Expression Determined Using Microarrays for Transcriptome Analysis

2001 ◽  
Vol 183 (24) ◽  
pp. 7329-7340 ◽  
Author(s):  
Robert Caldwell ◽  
Ron Sapolsky ◽  
Walter Weyler ◽  
Randal R. Maile ◽  
Stuart C. Causey ◽  
...  
Keyword(s):  
Gene Expression ◽  
Bacillus Subtilis ◽  
Expression Patterns ◽  
Global Scale ◽  
Complete Sequence ◽  
Dna Arrays ◽  
Genome Wide ◽  
Genes Encoding ◽  
Nucleoside Metabolism

ABSTRACT The availability of the complete sequence of the Bacillus subtilis chromosome (F. Kunst et al., Nature 390:249–256, 1997) makes possible the construction of genome-wide DNA arrays and the study of this organism on a global scale. Because we have a long-standing interest in the effects of scoC on late-stage developmental phenomena as they relate toaprE expression, we studied the genome-wide effects of ascoC null mutant with the goal of furthering the understanding of the role of scoC in growth and developmental processes. In the present work we compared the expression patterns of isogenic B. subtilis strains, one of which carries a null mutation in the scoC locus (scoC4). The results obtained indicate thatscoC regulates, either directly or indirectly, the expression of at least 560 genes in the B. subtilisgenome. ScoC appeared to repress as well as activate gene expression. Changes in expression were observed in genes encoding transport and binding proteins, those involved in amino acid, carbohydrate, and nucleotide and/or nucleoside metabolism, and those associated with motility, sporulation, and adaptation to atypical conditions. Changes in gene expression were also observed for transcriptional regulators, along with sigma factors, regulatory phosphatases and kinases, and members of sensor regulator systems. In this report, we discuss some of the phenotypes associated with the scoCmutant in light of the transcriptome changes observed.

scholarly journals Integration of transcriptome and methylome analysis of aldosterone-producing adenomas

2015 ◽  
Vol 173 (2) ◽  
pp. 185-195 ◽  
Author(s):  
Masanori Murakami ◽  
Takanobu Yoshimoto ◽  
Kazuhiko Nakabayashi ◽  
Kyoichiro Tsuchiya ◽  
Isao Minami ◽  
...  
Keyword(s):  
Gene Expression ◽  
Methylation Status ◽  
Japanese Patients ◽  
Integrated Analysis ◽  
Dna Hypomethylation ◽  
Genome Wide ◽  
Aldosterone Production ◽  
Methylome Analysis ◽  
The Relationship

ObjectiveThe pathophysiology of aldosterone-producing adenomas (APA) has been investigated intensively through genetic and genomic approaches. However, the role of epigenetics in APA is not fully understood. In the present study, we explored the relationship between gene expression and DNA methylation status in APA.MethodsWe conducted an integrated analysis of transcriptome and methylome data of paired APA-adjacent adrenal gland (AAG) samples from the same patient. The adrenal specimens were obtained from seven Japanese patients with APA who underwent adrenalectomy. Gene expression and genome-wide CpG methylation profiles were obtained from RNA and DNA samples that were extracted from those seven paired tissues.ResultsMethylome analysis showed global CpG hypomethylation in APA relative to AAG. The integration of gene expression and methylation status showed that 34 genes were up-regulated with CpG hypomethylation in APA. Of these, three genes (CYP11B2, MC2R, and HPX) may be related to aldosterone production, and five genes (PRRX1, RAB38, FAP, GCNT2, and ASB4) are potentially involved in tumorigenesis.ConclusionThe present study is the first methylome analysis to compare APA with AAG in the same patients. Our integrated analysis of transcriptome and methylome revealed DNA hypomethylation in APA and identified several up-regulated genes with DNA hypomethylation that may be involved in aldosterone production and tumorigenesis.

scholarly journals Multivariable regulation of gene expression plasticity in metazoans

2019 ◽  
Author(s):  
Long Xiao ◽  
Zhiguang Zhao ◽  
Fei He ◽  
Zhuo Du
Keyword(s):  
Gene Expression ◽  
Histone Modifications ◽  
Regulation Of Gene Expression ◽  
Rapid Change ◽  
High Plasticity ◽  
Expression Levels ◽  
Genome Wide ◽  
Expression Potential ◽  
Highly Correlated

ABSTRACTAn important capacity of genes is the rapid change of expression levels to cope with environment, known as expression plasticity. Elucidating the genomic mechanisms determining expression plasticity is critical for understanding the molecular basis of phenotypic plasticity, fitness, and adaptation. In this study, we systematically quantified genome-wide gene expression plasticity in four metazoan species by integrating changes of expression levels under a large number of genetic and environmental conditions. From this, we demonstrated that expression plasticity measures a distinct feature of gene expression that is orthogonal to other well-studies features including gene expression potential and tissue specificity/broadness. Expression plasticity is conserved across species with important physiological implications. The magnitude of expression plasticity is highly correlated with gene function and genes with high plasticity are implicated in disease susceptibility. Genome-wide analysis identified many conserved promoter cis-elements, trans-acting factors (such as CFCF), and gene body histone modifications (H3K36me3, H3K79me2, and H4K20me1) that are significantly associated with expression plasticity. Analysis of expression changes in perturbation experiments further validated a causal role of specific transcription factors and histone modifications. Collectively, this work reveals general properties, physiological implications, and multivariable regulation of gene expression plasticity in metazoans, extending the mechanistic understanding of gene regulation.

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