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1.
Sci Rep ; 9(1): 14938, 2019 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-31624306

RESUMO

Tardigrades, also known as water bears, are small aquatic animals that inhabit marine, fresh water or limno-terrestrial environments. While all tardigrades require surrounding water to grow and reproduce, species living in limno-terrestrial environments (e.g. Ramazzottius varieornatus) are able to undergo almost complete dehydration by entering an arrested state known as anhydrobiosis, which allows them to tolerate ionic radiation, extreme temperatures and intense pressure. Previous studies based on comparison of the genomes of R. varieornatus and Hypsibius dujardini - a less tolerant tardigrade - have pointed to potential mechanisms that may partially contribute to their remarkable ability to resist extreme physical conditions. In this work, we have further annotated the genomes of both tardigrades using a guided approach in search for novel mechanisms underlying the extremotolerance of R. varieornatus. We have found specific amplifications of several genes, including MRE11 and XPC, and numerous missense variants exclusive of R. varieornatus in CHEK1, POLK, UNG and TERT, all of them involved in important pathways for DNA repair and telomere maintenance. Taken collectively, these results point to genomic features that may contribute to the enhanced ability to resist extreme environmental conditions shown by R. varieornatus.

2.
Int J Mol Sci ; 20(5)2019 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-30823472

RESUMO

Given their endosymbiotic origin, chloroplasts and mitochondria genomes harbor only between 100 and 200 genes that encode the proteins involved in organellar gene expression (OGE), photosynthesis, and the electron transport chain. However, as the activity of these organelles also needs a few thousand proteins encoded by the nuclear genome, a close coordination of the gene expression between the nucleus and organelles must exist. In line with this, OGE regulation is crucial for plant growth and development, and is achieved mainly through post-transcriptional mechanisms performed by nuclear genes. In this way, the nucleus controls the activity of organelles and these, in turn, transmit information about their functional state to the nucleus by modulating nuclear expression according to the organelles' physiological requirements. This adjusts organelle function to plant physiological, developmental, or growth demands. Therefore, OGE must appropriately respond to both the endogenous signals and exogenous environmental cues that can jeopardize plant survival. As sessile organisms, plants have to respond to adverse conditions to acclimate and adapt to them. Salinity is a major abiotic stress that negatively affects plant development and growth, disrupts chloroplast and mitochondria function, and leads to reduced yields. Information on the effects that the disturbance of the OGE function has on plant tolerance to salinity is still quite fragmented. Nonetheless, many plant mutants which display altered responses to salinity have been characterized in recent years, and interestingly, several are affected in nuclear genes encoding organelle-localized proteins that regulate the expression of organelle genes. These results strongly support a link between OGE and plant salt tolerance, likely through retrograde signaling. Our review analyzes recent findings on the OGE functions required by plants to respond and tolerate salinity, and highlights the fundamental role that chloroplast and mitochondrion homeostasis plays in plant adaptation to salt stress.


Assuntos
Cloroplastos/genética , Regulação da Expressão Gênica de Plantas , Mitocôndrias/genética , Fenômenos Fisiológicos Vegetais , Estresse Salino , Cloroplastos/metabolismo , Mitocôndrias/metabolismo
3.
EMBO Mol Med ; 11(4)2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30862662

RESUMO

Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disorder caused by progerin, a mutant lamin A variant. HGPS patients display accelerated aging and die prematurely, typically from atherosclerosis complications. Recently, we demonstrated that progerin-driven vascular smooth muscle cell (VSMC) loss accelerates atherosclerosis leading to premature death in apolipoprotein E-deficient mice. However, the molecular mechanism underlying this process remains unknown. Using a transcriptomic approach, we identify here endoplasmic reticulum stress (ER) and the unfolded protein responses as drivers of VSMC death in two mouse models of HGPS exhibiting ubiquitous and VSMC-specific progerin expression. This stress pathway was also activated in HGPS patient-derived cells. Targeting ER stress response with a chemical chaperone delayed medial VSMC loss and inhibited atherosclerosis in both progeria models, and extended lifespan in the VSMC-specific model. Our results identify a mechanism underlying cardiovascular disease in HGPS that could be targeted in patients. Moreover, these findings may help to understand other vascular diseases associated with VSMC death, and provide insight into aging-dependent vascular damage related to accumulation of unprocessed toxic forms of lamin A.

4.
Nat Med ; 25(3): 423-426, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30778239

RESUMO

CRISPR/Cas9-based therapies hold considerable promise for the treatment of genetic diseases. Among these, Hutchinson-Gilford progeria syndrome, caused by a point mutation in the LMNA gene, stands out as a potential candidate. Here, we explore the efficacy of a CRISPR/Cas9-based approach that reverts several alterations in Hutchinson-Gilford progeria syndrome cells and mice by introducing frameshift mutations in the LMNA gene.


Assuntos
Sistemas CRISPR-Cas , Terapia Genética/métodos , Lamina Tipo A/genética , Progéria/terapia , Animais , Células HEK293 , Humanos , Lamina Tipo A/metabolismo , Camundongos , Mutação Puntual , Progéria/genética
10.
JAMA Dermatol ; 155(5): 604-609, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-30586141

RESUMO

Importance: The protection of telomeres 1 protein (POT1) is a critical component of the shelterin complex, a multiple-protein machine that regulates telomere length and protects telomere ends. Germline variants in POT1 have been linked to familial melanoma, and somatic mutations are associated with a range of cancers including cutaneous T-cell lymphoma (CTCL). Objective: To characterize pathogenic variation in POT1 in families with melanoma to inform clinical management. Design, Setting, and Participants: In this case study and pedigree evaluation, analysis of the pedigree of 1 patient with melanoma revealed a novel germline POT1 variant (p.I78T, c.233T>C, chromosome 7, g.124870933A>G, GRCh38) that was subsequently found in 2 other pedigrees obtained from the GenoMEL Consortium. Main Outcomes and Measures: (1) Identification of the POT1 p.I78T variant; (2) evaluation of the clinical features and characteristics of patients with this variant; (3) analysis of 3 pedigrees; (4) genomewide single-nucleotide polymorphism genotyping of germline DNA; and (5) a somatic genetic analysis of available nevi and 1 melanoma lesion. Results: The POT1 p.I78T variant was found in 3 melanoma pedigrees, all of persons who self-reported as being of Jewish descent, and was shown to disrupt POT1-telomere binding. A UV mutation signature was associated with nevus and melanoma formation in POT1 variant carriers, and somatic mutations in driver genes such as BRAF, NRAS, and KIT were associated with lesion development in these patients. Conclusions and Relevance: POT1 p.I78T is a newly identified, likely pathogenic, variant meriting screening for in families with melanoma after more common predisposition genes such as CDKN2A have been excluded. It could also be included as part of gene panel testing.

11.
Nat Ecol Evol ; 3(1): 87-95, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30510174

RESUMO

Giant tortoises are among the longest-lived vertebrate animals and, as such, provide an excellent model to study traits like longevity and age-related diseases. However, genomic and molecular evolutionary information on giant tortoises is scarce. Here, we describe a global analysis of the genomes of Lonesome George-the iconic last member of Chelonoidis abingdonii-and the Aldabra giant tortoise (Aldabrachelys gigantea). Comparison of these genomes with those of related species, using both unsupervised and supervised analyses, led us to detect lineage-specific variants affecting DNA repair genes, inflammatory mediators and genes related to cancer development. Our study also hints at specific evolutionary strategies linked to increased lifespan, and expands our understanding of the genomic determinants of ageing. These new genome sequences also provide important resources to help the efforts for restoration of giant tortoise populations.


Assuntos
Envelhecimento/genética , Genoma , Tartarugas/genética , Animais , Reparo do DNA/genética , Evolução Molecular , Células HEK293 , Humanos , Mediadores da Inflamação , Masculino , Neoplasias/genética , Filogenia , Densidade Demográfica
12.
Methods Mol Biol ; 1881: 319-325, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30350214

RESUMO

The genomic sequencing of chronic lymphocytic leukemia (CLL) samples has provided exciting new venues for the understanding and treatment of this prevalent disease. This feat is possible thanks to high-throughput sequencing methods, such as Illumina sequencing. The interpretation of these data sources requires not only appropriate software and hardware, but also understanding the biology and technology behind the sequencing process. Here, we provide a primer to understand each step in the analysis of point mutations from whole-genome or whole-exome sequencing experiments of tumor and normal samples.


Assuntos
Biologia Computacional/métodos , Variação Genética , Genoma Humano , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Leucemia Linfocítica Crônica de Células B/genética , Análise de Sequência de DNA/métodos , Sequenciamento Completo do Genoma/métodos , Humanos , Software
13.
Cancer Res ; 78(21): 6320-6328, 2018 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-30232219

RESUMO

With the advent of OMICs technologies, both individual research groups and consortia have spear-headed the characterization of human samples of multiple pathophysiologic origins, resulting in thousands of archived genomes and transcriptomes. Although a variety of web tools are now available to extract information from OMICs data, their utility has been limited by the capacity of nonbioinformatician researchers to exploit the information. To address this problem, we have developed CANCERTOOL, a web-based interface that aims to overcome the major limitations of public transcriptomics dataset analysis for highly prevalent types of cancer (breast, prostate, lung, and colorectal). CANCERTOOL provides rapid and comprehensive visualization of gene expression data for the gene(s) of interest in well-annotated cancer datasets. This visualization is accompanied by generation of reports customized to the interest of the researcher (e.g., editable figures, detailed statistical analyses, and access to raw data for reanalysis). It also carries out gene-to-gene correlations in multiple datasets at the same time or using preset patient groups. Finally, this new tool solves the time-consuming task of performing functional enrichment analysis with gene sets of interest using up to 11 different databases at the same time. Collectively, CANCERTOOL represents a simple and freely accessible interface to interrogate well-annotated datasets and obtain publishable representations that can contribute to refinement and guidance of cancer-related investigations at all levels of hypotheses and design.Significance: In order to facilitate access of research groups without bioinformatics support to public transcriptomics data, we have developed a free online tool with an easy-to-use interface that allows researchers to obtain quality information in a readily publishable format. Cancer Res; 78(21); 6320-8. ©2018 AACR.


Assuntos
Biologia Computacional/métodos , Neoplasias/genética , Algoritmos , Gráficos por Computador , Bases de Dados Factuais , Bases de Dados Genéticas , Genômica , Humanos , Internet , Oncologia , Proteômica , Software , Transcriptoma , Interface Usuário-Computador , Fluxo de Trabalho
14.
Blood ; 132(22): 2375-2388, 2018 11 29.
Artigo em Inglês | MEDLINE | ID: mdl-30181176

RESUMO

Genomic studies have recently identified RPS15 as a new driver gene in aggressive and chemorefractory cases of chronic lymphocytic leukemia (CLL). RPS15 encodes a ribosomal protein whose conserved C-terminal domain extends into the decoding center of the ribosome. We demonstrate that mutations in highly conserved residues of this domain affect protein stability, by increasing its ubiquitin-mediated degradation, and cell-proliferation rates. On the other hand, we show that mutated RPS15 can be loaded into the ribosomes, directly impacting on global protein synthesis and/or translational fidelity in a mutation-specific manner. Quantitative mass spectrometry analyses suggest that RPS15 variants may induce additional alterations in the translational machinery, as well as a metabolic shift at the proteome level in HEK293T and MEC-1 cells. These results indicate that CLL-related RPS15 mutations might act following patterns known for other ribosomal diseases, likely switching from a hypo- to a hyperproliferative phenotype driven by mutated ribosomes. In this scenario, loss of translational fidelity causing altered cell proteostasis can be proposed as a new molecular mechanism involved in CLL pathobiology.


Assuntos
Leucemia Linfocítica Crônica de Células B/genética , Mutação , Proteínas Ribossômicas/genética , Ribossomos/genética , Linhagem Celular Tumoral , Estudos de Coortes , Células HEK293 , Humanos , Leucemia Linfocítica Crônica de Células B/patologia , Taxa de Mutação , Mutação Puntual , Biossíntese de Proteínas , Domínios Proteicos , Proteínas Ribossômicas/química , Ribossomos/patologia
15.
Int J Mol Sci ; 19(8)2018 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-30110886

RESUMO

Exposure of plants to abiotic stresses, such as salinity, cold, heat, or drought, affects their growth and development, and can significantly reduce their productivity. Plants have developed adaptive strategies to deal with situations of abiotic stresses with guarantees of success, which have favoured the expansion and functional diversification of different gene families. The family of mitochondrial transcription termination factors (mTERFs), first identified in animals and more recently in plants, is likely a good example of this. In plants, mTERFs are located in chloroplasts and/or mitochondria, participate in the control of organellar gene expression (OGE), and, compared with animals, the mTERF family is expanded. Furthermore, the mutations in some of the hitherto characterised plant mTERFs result in altered responses to salt, high light, heat, or osmotic stress, which suggests a role for these genes in plant adaptation and tolerance to adverse environmental conditions. In this work, we investigated the effect of impaired mTERF6 function on the tolerance of Arabidopsis to salt, osmotic and moderate heat stresses, and on the response to the abscisic acid (ABA) hormone, required for plants to adapt to abiotic stresses. We found that the strong loss-of-function mterf6-2 and mterf6-5 mutants, mainly the former, were hypersensitive to NaCl, mannitol, and ABA during germination and seedling establishment. Additionally, mterf6-5 exhibited a higher sensitivity to moderate heat stress and a lower response to NaCl and ABA later in development. Our computational analysis revealed considerable changes in the mTERF6 transcript levels in plants exposed to different abiotic stresses. Together, our results pinpoint a function for Arabidopsis mTERF6 in the tolerance to adverse environmental conditions, and highlight the importance of plant mTERFs, and hence of OGE homeostasis, for proper acclimation to abiotic stress.


Assuntos
Aclimatação , Proteínas de Arabidopsis/metabolismo , Arabidopsis/metabolismo , Fatores de Transcrição de Zíper de Leucina Básica/metabolismo , Germinação , Resposta ao Choque Térmico , Proteínas Mitocondriais/metabolismo , Mutação , Plântula/metabolismo , Arabidopsis/genética , Proteínas de Arabidopsis/genética , Fatores de Transcrição de Zíper de Leucina Básica/genética , Proteínas Mitocondriais/genética , Plântula/genética
18.
Bioinformatics ; 34(13): 2322-2324, 2018 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-29949954

RESUMO

Motivation: Venn and Euler diagrams are extensively used for the visualization of relationships between experiments and datasets. However, representing more than three datasets while keeping the proportions of each region is still not feasible with existing tools. Results: We present an algorithm to render all the regions of a generalized n-dimensional Venn diagram, while keeping the area of each region approximately proportional to the number of elements included. In addition, missing regions in Euler diagrams lead to simplified representations. The algorithm generates an n-dimensional Venn diagram and inserts circles of given areas in each region. Then, the diagram is rearranged with a dynamic, self-correcting simulation in which each set border is contracted until it contacts the circles inside. This algorithm is implemented in a C++ tool (nVenn) with or without a web interface. The web interface also provides the ability to analyze the regions of the diagram. Availability and implementation: The source code and pre-compiled binaries of nVenn are available at https://github.com/vqf/nVenn. A web interface for up to six sets can be accessed at http://degradome.uniovi.es/cgi-bin/nVenn/nvenn.cgi. Supplementary information: Supplementary data are available at Bioinformatics online.


Assuntos
Software , Algoritmos
19.
Plant Sci ; 266: 117-129, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29241561

RESUMO

To enhance our understanding of the roles of mitochondrial transcription termination factors (mTERFs) in plants, we have taken a reverse genetic approach in Arabidopsis thaliana. One of the mutants isolated carried a novel allele of the mTERF6 gene, which we named mterf6-5. mTERF6 is a chloroplast and mitochondrial localised protein required for the maturation of chloroplast isoleucine tRNA. The mterf6-5 plants are pale and exhibit markedly reduced growth, and altered leaf and chloroplast development. Our qRT-PCR analyses revealed mis-expression of several plastid, mitochondrial and nuclear genes in mterf6-5 plants. Synergistic phenotypes were observed in double mutant combinations of mterf6-5 with alleles of other mTERF genes as well as with scabra3-2, affected in the plastid RpoTp RNA polymerase; these observations suggest a functional relationship between mTERF6, other mTERFs and SCA3. The mterf6-5 mutation also enhanced the leaf dorsoventral polarity defects of the asymmetric leaves1-1 (as1-1) mutant, which resulted in radial leaves. This interaction seemed specific of the impaired mTERF6 function because mutations in the mTERF genes MDA1 or TWR-1/mTERF9 did not result in radialised leaves. Furthermore, the mterf6-5 mutation dramatically increased the leaf phenotype of as2-1 and caused lethality early in vegetative development. Our results uncover a new role for mTERF6 in leaf patterning and highlight the importance of mTERFs in plant development.


Assuntos
Proteínas de Arabidopsis/genética , Arabidopsis/genética , Fatores de Transcrição de Zíper de Leucina Básica/genética , Proteínas Mitocondriais/genética , Folhas de Planta/genética , Arabidopsis/crescimento & desenvolvimento , Proteínas de Arabidopsis/metabolismo , Fatores de Transcrição de Zíper de Leucina Básica/metabolismo , Proteínas Mitocondriais/metabolismo , Fenótipo , Folhas de Planta/crescimento & desenvolvimento
20.
Int J Mol Sci ; 18(12)2017 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-29207474

RESUMO

Mitochondria are the powerhouse of eukaryotic cells because they are responsible for energy production through the aerobic respiration required for growth and development. These organelles harbour their own genomes and translational apparatus: mitochondrial ribosomes or mitoribosomes. Deficient mitochondrial translation would impair the activity of this organelle, and is expected to severely perturb different biological processes of eukaryotic organisms. In plants, mitoribosomes consist of three rRNA molecules, encoded by the mitochondrial genome, and an undefined set of ribosomal proteins (mitoRPs), encoded by nuclear and organelle genomes. A detailed functional and structural characterisation of the mitochondrial translation apparatus in plants is currently lacking. In some plant species, presence of small gene families of mitoRPs whose members have functionally diverged has led to the proposal of the heterogeneity of the mitoribosomes. This hypothesis supports a dynamic composition of the mitoribosomes. Information on the effects of the impaired function of mitoRPs on plant development is extremely scarce. Nonetheless, several works have recently reported the phenotypic and molecular characterisation of plant mutants affected in mitoRPs that exhibit alterations in specific development aspects, such as embryogenesis, leaf morphogenesis or the formation of reproductive tissues. Some of these results would be in line with the ribosomal filter hypothesis, which proposes that ribosomes, besides being the machinery responsible for performing translation, are also able to regulate gene expression. This review describes the phenotypic effects on plant development displayed by the mutants characterised to date that are defective in genes which encode mitoRPs. The elucidation of plant mitoRPs functions will provide a better understanding of the mechanisms that control organelle gene expression and their contribution to plant growth and morphogenesis.


Assuntos
Ribossomos Mitocondriais/metabolismo , Desenvolvimento Vegetal , Plantas/metabolismo , Proteínas Ribossômicas/genética , Regulação da Expressão Gênica no Desenvolvimento , Regulação da Expressão Gênica de Plantas , Família Multigênica , Mutação , Fenótipo , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Plantas/genética , Proteínas Ribossômicas/metabolismo
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