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1.
Cell ; 153(7): 1537-51, 2013 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-23791181

RESUMO

In mammals, dosage compensation between XX and XY individuals occurs through X chromosome inactivation (XCI). The noncoding Xist RNA is expressed and initiates XCI only when more than one X chromosome is present. Current models invoke a dependency on the X-to-autosome ratio (X:A), but molecular factors remain poorly defined. Here, we demonstrate that molecular titration between an X-encoded RNA and an autosomally encoded protein dictates Xist induction. In pre-XCI cells, CTCF protein represses Xist transcription. At the onset of XCI, Jpx RNA is upregulated, binds CTCF, and extricates CTCF from one Xist allele. We demonstrate that CTCF is an RNA-binding protein and is titrated away from the Xist promoter by Jpx RNA. Thus, Jpx activates Xist by evicting CTCF. The functional antagonism via molecular titration reveals a role for long noncoding RNA in epigenetic regulation.


Assuntos
RNA Longo não Codificante/metabolismo , Proteínas Repressoras/metabolismo , Regulação para Cima , Inativação do Cromossomo X , Animais , Fator de Ligação a CCCTC , Cromossomos de Mamíferos/metabolismo , Células-Tronco Embrionárias/metabolismo , Feminino , Masculino , Camundongos , Regiões Promotoras Genéticas , RNA Longo não Codificante/genética , Cromossomo X/metabolismo
2.
Mol Cell ; 77(1): 1-2, 2020 01 02.
Artigo em Inglês | MEDLINE | ID: mdl-31951515

RESUMO

In a recent issue of Molecular Cell, Natarajan et al. (2020) showed that unassembled ER membrane proteins diffuse to the INM for degradation. The INM-localized Asi E3 ligase complex is sufficient and necessary for recognition and ubiquitination of unassembled ER membrane proteins.


Assuntos
Proteínas de Membrana , Membrana Nuclear , Núcleo Celular , Retículo Endoplasmático , Controle de Qualidade , Ubiquitinação
3.
Nat Chem Biol ; 19(4): 468-477, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-36635564

RESUMO

Membrane dynamics are important to the integrity and function of mitochondria. Defective mitochondrial fusion underlies the pathogenesis of multiple diseases. The ability to target fusion highlights the potential to fight life-threatening conditions. Here we report a small molecule agonist, S89, that specifically promotes mitochondrial fusion by targeting endogenous MFN1. S89 interacts directly with a loop region in the helix bundle 2 domain of MFN1 to stimulate GTP hydrolysis and vesicle fusion. GTP loading or competition by S89 dislodges the loop from the GTPase domain and unlocks the molecule. S89 restores mitochondrial and cellular defects caused by mitochondrial DNA mutations, oxidative stress inducer paraquat, ferroptosis inducer RSL3 or CMT2A-causing mutations by boosting endogenous MFN1. Strikingly, S89 effectively eliminates ischemia/reperfusion (I/R)-induced mitochondrial damage and protects mouse heart from I/R injury. These results reveal the priming mechanism for MFNs and provide a therapeutic strategy for mitochondrial diseases when additional mitochondrial fusion is beneficial.


Assuntos
Dinâmica Mitocondrial , Proteínas de Transporte da Membrana Mitocondrial , Camundongos , Animais , Proteínas de Transporte da Membrana Mitocondrial/análise , Proteínas de Transporte da Membrana Mitocondrial/química , Proteínas de Transporte da Membrana Mitocondrial/genética , Mitocôndrias , Hidrólise , Guanosina Trifosfato/análise , Guanosina Trifosfato/farmacologia , Proteínas Mitocondriais/genética , Proteínas Mitocondriais/análise , Proteínas Mitocondriais/farmacologia
4.
Cell ; 143(3): 390-403, 2010 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-21029862

RESUMO

Once protein-coding, the X-inactivation center (Xic) is now dominated by large noncoding RNAs (ncRNA). X chromosome inactivation (XCI) equalizes gene expression between mammalian males and females by inactivating one X in female cells. XCI requires Xist, an ncRNA that coats the X and recruits Polycomb proteins. How Xist is controlled remains unclear but likely involves negative and positive regulators. For the active X, the antisense Tsix RNA is an established Xist repressor. For the inactive X, here, we identify Xic-encoded Jpx as an Xist activator. Jpx is developmentally regulated and accumulates during XCI. Deleting Jpx blocks XCI and is female lethal. Posttranscriptional Jpx knockdown recapitulates the knockout, and supplying Jpx in trans rescues lethality. Thus, Jpx is trans-acting and functions as ncRNA. Furthermore, ΔJpx is rescued by truncating Tsix, indicating an antagonistic relationship between the ncRNAs. We conclude that Xist is controlled by two RNA-based switches: Tsix for Xa and Jpx for Xi.


Assuntos
RNA não Traduzido/genética , Inativação do Cromossomo X , Animais , Linhagem Celular , Células-Tronco Embrionárias , Feminino , Genes Letais , Humanos , Masculino , Camundongos , RNA Longo não Codificante , RNA não Traduzido/metabolismo
5.
Hum Genet ; 2023 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-38095719

RESUMO

The prevalence and progression of cancer differ in males and females, and thus, sexual dimorphism in tumor development directly impacts clinical research and medicine. Long non-coding RNAs (lncRNAs) are increasingly recognized as important players in gene expression and various cellular processes, including cancer development and progression. In recent years, lncRNAs have been implicated in the differences observed in cancer incidence, progression, and treatment responses between men and women. Here, we present a brief overview of the current knowledge regarding the role of lncRNAs in cancer sex dimorphism, focusing on how they affect epigenetic processes in male and female mammalian cells. We discuss the potential mechanisms by which lncRNAs may contribute to sex differences in cancer, including transcriptional control of sex chromosomes, hormonal signaling pathways, and immune responses. We also propose strategies for studying lncRNA functions in cancer sex dimorphism. Furthermore, we emphasize the importance of considering sex as a biological variable in cancer research and the need to investigate the role lncRNAs play in mediating these sex differences. In summary, we highlight the emerging link between lncRNAs and cancer sex dimorphism and their potential as therapeutic targets.

6.
Int J Mol Sci ; 24(4)2023 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-36835631

RESUMO

Epilepsy is a neurological disorder characterized by hypersynchronous recurrent neuronal activities and seizures, as well as loss of muscular control and sometimes awareness. Clinically, seizures have been reported to display daily variations. Conversely, circadian misalignment and circadian clock gene variants contribute to epileptic pathogenesis. Elucidation of the genetic bases of epilepsy is of great importance because the genetic variability of the patients affects the efficacies of antiepileptic drugs (AEDs). For this narrative review, we compiled 661 epilepsy-related genes from the PHGKB and OMIM databases and classified them into 3 groups: driver genes, passenger genes, and undetermined genes. We discuss the potential roles of some epilepsy driver genes based on GO and KEGG analyses, the circadian rhythmicity of human and animal epilepsies, and the mutual effects between epilepsy and sleep. We review the advantages and challenges of rodents and zebrafish as animal models for epileptic studies. Finally, we posit chronomodulated strategy-based chronotherapy for rhythmic epilepsies, integrating several lines of investigation for unraveling circadian mechanisms underpinning epileptogenesis, chronopharmacokinetic and chronopharmacodynamic examinations of AEDs, as well as mathematical/computational modeling to help develop time-of-day-specific AED dosing schedules for rhythmic epilepsy patients.


Assuntos
Epilepsia , Peixe-Zebra , Animais , Humanos , Epilepsia/tratamento farmacológico , Convulsões/tratamento farmacológico , Anticonvulsivantes/farmacologia , Ritmo Circadiano/genética
7.
Int J Mol Sci ; 24(7)2023 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-37047373

RESUMO

Temporal lobe epilepsy (TLE) is a common and severe epilepsy displaying rhythmicity in humans and animals. However, how the circadian clock contributes to TLE remains elusive. A recent circadian analysis of the ventral hippocampal transcriptome of pilocarpine-induced TLE mice revealed as many as 1650 rhythmically expressed transcripts. Here, a comparison of the mouse ventral hippocampal transcriptome with the human epilepsy-related gene set identified 315 possible mouse epilepsy-related genes. Rhythmicity analysis classified them into arrhythmicity, loss-of-rhythmicity, gain-of-rhythmicity, and rhythmicity-maintaining groups. KEGG and GO analyses of these mouse epilepsy genes suggest their involvement in circadian entrainment. In TLE mice, Htr1d, Drd2, and Chrna3 lose rhythmicity, but P2rx7 gains rhythmicity; the up-regulation of Htr1d and Drd2 and down-regulation of Chrna3 inhibit adenylate cyclase (AC), and up-regulation of Htr1d, Drd2, and P2rx7 activates protein kinase C (PKC). Together, these results suggest that epilepsy can disrupt the circadian dynamics of the epileptic genes, shed light on possible TLE pathogenesis, and provide potential targets for TLE diagnosis and chronotherapy.


Assuntos
Epilepsia do Lobo Temporal , Epilepsia , Camundongos , Humanos , Animais , Epilepsia do Lobo Temporal/induzido quimicamente , Epilepsia do Lobo Temporal/genética , Epilepsia do Lobo Temporal/metabolismo , Epilepsia/metabolismo , Pilocarpina/toxicidade , Hipocampo/metabolismo , Regulação para Cima
8.
Entropy (Basel) ; 25(7)2023 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-37509988

RESUMO

Spatially coupled low density parity check (SC-LDPC) are prominent candidates for future communication standards due to their "threshold saturation" properties. To evaluate the finite-length performance of SC-LDPC codes, a general and efficient finite-length analysis from the perspective of the base matrix is proposed. We analyze the evolution of the residual graphs resulting at each iteration during the decoding process based on the base matrix and then derive the expression for the error probability. To verify the effectiveness of the proposed finite-length analysis, we consider the SC-LDPC code ensembles constructed by parallelly connecting multiple chains (PC-MSC-LDPC). The analysis results show that the predicted error probabilities obtained by using the derived expression for the error probability match the simulated error probabilities. The proposed finite-length analysis provides a useful engineering tool for practical SC-LDPC code design and for analyzing the effects of the code parameters on the performances.

9.
Small ; 18(49): e2204996, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36287092

RESUMO

DNA nanotubes with prescribed geometry could allow for nanomaterial organization with designed optical or electrical function. As one of the dominating driving forces for DNA nanotube assembly, intrinsic curvature and twist of building blocks can be induced by bending deformation and twisting deformation. However, it is still unknown that how bending and twisting design on nanoscale building blocks affects the geometry of DNA tubes with micrometer length. Here, through targeted base pair deletion or insertion, the amount of bending deformation in building blocks is modulated by length gradient and the amount of twisting deformation is modulated by average twist density. This work systematically explores the independent effect and synergistic effect of two types of deformation on tube geometry, including diameter, chirality, and helical angles, via a streptavidin-labeling technique. The design rules enable the construction of DNA nanotubes with prescribed chirality and tailored diameters.


Assuntos
DNA
10.
J Membr Biol ; 255(6): 723-732, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-35596004

RESUMO

Mammalian placenta formation requires continuous fusion of trophoblasts. Human endogenous retrovirus-derived proteins syncytin-1 and syncytin-2 mediate cell-cell fusion of placental cytotrophoblasts to form syncytiotrophoblasts in primates, which is required for normal placenta function and fetal development. Syncytins are post-translationally cleaved by the endoprotease furin into surface (SU) and transmembrane (TM) subunits for activation. Little is currently known about the molecular mechanisms of syncytin-mediated cell-cell fusion, and their functions have not been well studied in vitro. Here, we express tagged syncytin-2 in mammalian HEK293T cells and demonstrate that the tagging greatly influences the cleavage and fusogenic activity of syncytin-2. By detecting the N-terminal tagged SU, we find that it is released into the extracellular space during the fusion process. Furthermore, when N-linked glycosylation and disulfide bond formation are blocked, the cleavage and fusogenic activity of syncytin-2 are inhibited. Finally, we were able to purify functional syncytin-2 from HEK293T cells and incorporate it into proteoliposomes. These findings lay a solid foundation for interogating the molecular mechanisms of syncytin-2-mediated cell-cell fusion in vitro.


Assuntos
Placenta , Proteínas da Gravidez , Animais , Humanos , Feminino , Gravidez , Placenta/metabolismo , Células HEK293 , Produtos do Gene env/química , Produtos do Gene env/metabolismo , Proteínas da Gravidez/química , Proteínas da Gravidez/metabolismo , Trofoblastos/metabolismo , Mamíferos/metabolismo
11.
Proc Natl Acad Sci U S A ; 116(37): 18423-18428, 2019 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-31444302

RESUMO

During prophase I of meiosis, chromosomes become organized as loop arrays around the proteinaceous chromosome axis. As homologous chromosomes physically pair and recombine, the chromosome axis is integrated into the tripartite synaptonemal complex (SC) as this structure's lateral elements (LEs). While the components of the mammalian chromosome axis/LE-including meiosis-specific cohesin complexes, the axial element proteins SYCP3 and SYCP2, and the HORMA domain proteins HORMAD1 and HORMAD2-are known, the molecular organization of these components within the axis is poorly understood. Here, using expansion microscopy coupled with 2-color stochastic optical reconstruction microscopy (STORM) imaging (ExSTORM), we address these issues in mouse spermatocytes at a resolution of 10 to 20 nm. Our data show that SYCP3 and the SYCP2 C terminus, which are known to form filaments in vitro, form a compact core around which cohesin complexes, HORMADs, and the N terminus of SYCP2 are arrayed. Overall, our study provides a detailed structural view of the meiotic chromosome axis, a key organizational and regulatory component of meiotic chromosomes.


Assuntos
Cromossomos de Mamíferos/química , Cromossomos de Mamíferos/metabolismo , Microscopia/métodos , Animais , Proteínas de Ciclo Celular/metabolismo , Proteínas de Ligação a DNA/metabolismo , Masculino , Mamíferos/genética , Meiose , Camundongos , Espermatócitos/metabolismo , Coloração e Rotulagem , Complexo Sinaptonêmico/metabolismo
12.
J Biol Chem ; 295(46): 15498-15510, 2020 11 13.
Artigo em Inglês | MEDLINE | ID: mdl-32878985

RESUMO

A large number of newly synthesized membrane proteins in the endoplasmic reticulum (ER) are assembled into multiprotein complexes, but little is known about the mechanisms required for assembly membrane proteins. It has been suggested that membrane chaperones might exist, akin to the molecular chaperones that stabilize and direct the assembly of soluble protein complexes, but the mechanisms by which these proteins would bring together membrane protein components is unclear. Here, we have identified that the tail length of the C-terminal transmembrane domains (C-TMDs) determines efficient insertion and assembly of membrane proteins in the ER. We found that membrane proteins with C-TMD tails shorter than ∼60 amino acids are poorly inserted into the ER membrane, which suggests that translation is terminated before they are recognized by the Sec61 translocon for insertion. These C-TMDs with insufficient hydrophobicity are post-translationally recognized and retained by the Sec61 translocon complex, providing a time window for efficient assembly with TMDs from partner proteins. Retained TMDs that fail to assemble with their cognate TMDs are slowly translocated into the ER lumen and are recognized by the ER-associated degradation (ERAD) pathway for removal. In contrast, C-TMDs with sufficient hydrophobicity or tails longer than ∼80 residues are quickly released from the Sec61 translocon into the membrane or the ER lumen, resulting in inefficient assembly with partner TMDs. Thus, our data suggest that C-terminal tails harbor crucial signals for both the insertion and assembly of membrane proteins.


Assuntos
Membranas Intracelulares/metabolismo , Proteínas de Membrana/metabolismo , Sequência de Aminoácidos , Retículo Endoplasmático/metabolismo , Edição de Genes , Células HEK293 , Hexosiltransferases/química , Hexosiltransferases/metabolismo , Humanos , Interações Hidrofóbicas e Hidrofílicas , Proteínas de Membrana/química , Mutagênese Sítio-Dirigida , Proteínas Nucleares/química , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Domínios Proteicos , Transporte Proteico , Canais de Translocação SEC/química , Canais de Translocação SEC/metabolismo
13.
PLoS Genet ; 14(5): e1007378, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29734339

RESUMO

Mammalian X chromosome dosage compensation balances X-linked gene products between sexes and is coordinated by the long noncoding RNA (lncRNA) Xist. Multiple cis and trans-acting factors modulate Xist expression; however, the primary competence factor responsible for activating Xist remains a subject of dispute. The lncRNA Jpx is a proposed competence factor, yet it remains unknown if Jpx is sufficient to activate Xist expression in mice. Here, we utilize a novel transgenic mouse system to demonstrate a dose-dependent relationship between Jpx copy number and ensuing Jpx and Xist expression. By localizing transcripts of Jpx and Xist using RNA Fluorescence in situ Hybridization (FISH) in mouse embryonic cells, we provide evidence of Jpx acting in both trans and cis to activate Xist. Our data contribute functional and mechanistic insight for lncRNA activity in mice, and argue that Jpx is a competence factor for Xist activation in vivo.


Assuntos
Regulação da Expressão Gênica , Modelos Genéticos , RNA Longo não Codificante/genética , Animais , Células Cultivadas , Feminino , Fibroblastos/metabolismo , Hibridização in Situ Fluorescente , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Células-Tronco Embrionárias Murinas/metabolismo
14.
J Cell Physiol ; 235(4): 3258-3269, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31608989

RESUMO

This review aims to summarize and discuss the most recent advances in our understanding of the underlying mechanisms of the paradoxical effects of sortilin on lipid metabolism. The vacuolar protein sorting 10 protein (Vps10p) domain in the sortilin protein is responsible for substrate binding. Its cytoplasmic tail interacts with adaptor molecules, and modifications can determine whether sortilin trafficking occurs via the anterograde or retrograde pathway. The complicated trafficking behaviors likely contribute to the paradoxical roles of sortilin in lipid metabolism. The anterograde pathway of sortilin trafficking in hepatocytes, enterocytes, and peripheral cells likely causes an increase in plasma lipid levels, while the retrograde pathway leads to the opposite effect. Hepatocyte sortilin functions via the anterograde or retrograde pathway in a complicated and paradoxical manner to regulate apoB-containing lipoprotein metabolism. Clarifying the regulatory mechanisms underlying the trafficking behaviors of sortilin is necessary and may lead to artificial sortilin intervention as a potential therapeutic strategy for lipid disorder diseases. Conclusively, the paradoxical regulation of sortilin in lipid metabolism is likely due to its complicated trafficking behaviors.


Assuntos
Proteínas Adaptadoras de Transporte Vesicular/genética , Apolipoproteínas B/genética , Metabolismo dos Lipídeos/genética , Transporte Proteico/genética , Proteínas Adaptadoras de Transporte Vesicular/metabolismo , Apolipoproteínas B/metabolismo , Enterócitos/metabolismo , Hepatócitos/metabolismo , Humanos
16.
J Am Chem Soc ; 141(50): 19524-19528, 2019 12 18.
Artigo em Inglês | MEDLINE | ID: mdl-31789023

RESUMO

Synthesizing tubes of large diameters is important for materials science and nanotechnology but remains a largely unsolved challenge. We report herein an approach to program the width of DNA helical tubes by controlling the rigidity and curvature of repeating units via single-stranded bricks strategy. The rigidity of repeating units can be controlled by its thickness, and the curvature can be tuned by double-helical twist density. A single-step annealing allows for the fabrication of helical tubes with defined chirality and widths ranging from ∼50 to ∼550 nm.


Assuntos
DNA/química , Nanotubos/química , Modelos Moleculares , Conformação Molecular , Estereoisomerismo
17.
Acta Biochim Biophys Sin (Shanghai) ; 51(5): 471-483, 2019 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-30950489

RESUMO

Sortilin is closely associated with hyperlipidemia and the risk of atherosclerosis (AS). The role of sortilin and the underlying mechanism in peripheral macrophage are not fully understood. In this study, we investigated the effect of macrophage sortilin on ATP-binding cassette transporter A1 (ABCA1) expression, ABCA1-mediated cholesterol efflux, and aortic AS. Macrophage sortilin expression was upregulated by oxidized low-density lipoproteins (ox-LDLs) in both concentration- and time-dependent manners. Its expression reached the peak level when cells were incubated with 50 µg/ml ox-LDL for 24 h. Overexpression of sortilin in macrophage reduced cholesterol efflux, leading to an increase in intracellular total cholesterol, free cholesterol, and cholesterol ester. Sortilin was found to bind with ABCA1 protein and suppress macrophage ABCA1 expression, resulting in a decrease in cholesterol efflux from macrophages. The inhibitory effect of sortilin in cholesterol efflux was partially reversed by treatment with chloroquine, a lysosomal inhibitor. On the contrary, the ABCA1 protein level and ABCA1-mediated cholesterol efflux is increased by sortilin short hairpin RNA transfection. The fecal and biliary cholesterol 3H-sterol from cholesterol-laden mouse peritoneal macrophage was reduced by sortilin overexpression through lentivirus vector (LV)-sortilin in low-density lipoprotein receptor knockout mice, which was prevented by co-treatment with chloroquine. Treatment with LV-sortilin reduced plasma high-density lipoprotein and increased plasma ox-LDL levels. Accordingly, aortic lipid deposition and plaque area were exacerbated, and ABCA1 expression was reduced in mice in response to infection with LV-sortilin alone. These effects of LV-sortilin were partially reversed by chloroquine. Sortilin enhances lysosomal degradation of ABCA1 protein and suppresses ABCA1-mediated cholesterol efflux from macrophages, leading to foam cell formation and AS development.


Assuntos
Transportador 1 de Cassete de Ligação de ATP/metabolismo , Proteínas Adaptadoras de Transporte Vesicular/metabolismo , Aterosclerose/metabolismo , Colesterol/metabolismo , Lisossomos/metabolismo , Macrófagos/metabolismo , Transportador 1 de Cassete de Ligação de ATP/genética , Proteínas Adaptadoras de Transporte Vesicular/genética , Animais , Doenças da Aorta/genética , Doenças da Aorta/metabolismo , Aterosclerose/genética , Células Cultivadas , Células Espumosas/efeitos dos fármacos , Células Espumosas/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Lipoproteínas LDL/farmacologia , Macrófagos/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Interferência de RNA , Receptores de LDL/genética , Receptores de LDL/metabolismo , Células THP-1
18.
Bioinformatics ; 33(13): 2029-2031, 2017 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-28334276

RESUMO

MOTIVATION: RNA plays a critical role in gene expression and its regulation. RNA binding proteins (RBPs), in turn, are important regulators of RNA. Thanks to the availability of large scale data for RBP binding motifs and in vivo binding sites results in the form of eCLIP experiments, it is now possible to computationally predict RBP binding sites across the whole genome. RESULTS: We describe MotifMap-RNA, an extension of MotifMap which predicts binding sites for RBP motifs across human and mouse genomes and allows large scale querying of predicted binding sites. AVAILABILITY AND IMPLEMENTATION: The data and corresponding web server are available from: http://motifmap-rna.ics.uci.edu/ as part of the MotifMap web portal. CONTACT: rspitale@uci.edu or pfbaldi@uci.edu. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.


Assuntos
DNA/metabolismo , Genoma , Genômica/métodos , Proteínas de Ligação a RNA/metabolismo , Software , Animais , Sítios de Ligação , Regulação da Expressão Gênica , Humanos , Camundongos , Análise de Sequência de DNA
19.
Proc Natl Acad Sci U S A ; 112(47): 14415-22, 2015 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-26489649

RESUMO

The long noncoding X-inactivation-specific transcript (Xist gene) is responsible for mammalian X-chromosome dosage compensation between the sexes, the process by which one of the two X chromosomes is inactivated in the female soma. Xist is essential for both the random and imprinted forms of X-chromosome inactivation. In the imprinted form, Xist is paternally marked to be expressed in female embryos. To investigate the mechanism of Xist imprinting, we introduce Xist transgenes (Tg) into the male germ line. Although ectopic high-level Xist expression on autosomes can be compatible with viability, transgenic animals demonstrate reduced fitness, subfertility, defective meiotic pairing, and other germ-cell abnormalities. In the progeny, paternal-specific expression is recapitulated by the 200-kb Xist Tg. However, Xist imprinting occurs efficiently only when it is in an unpaired or unpartnered state during male meiosis. When transmitted from a hemizygous father (+/Tg), the Xist Tg demonstrates paternal-specific expression in the early embryo. When transmitted by a homozygous father (Tg/Tg), the Tg fails to show imprinted expression. Thus, Xist imprinting is directed by sequences within a 200-kb X-linked region, and the hemizygous (unpaired) state of the Xist region promotes its imprinting in the male germ line.


Assuntos
Impressão Genômica , Células Germinativas/metabolismo , RNA Longo não Codificante/genética , Animais , Blastocisto/metabolismo , Epigênese Genética , Feminino , Hemizigoto , Infertilidade Masculina/genética , Infertilidade Masculina/patologia , Masculino , Camundongos Transgênicos , Fenótipo , RNA Longo não Codificante/síntese química , RNA Longo não Codificante/metabolismo , Transgenes
20.
J Immunol ; 195(10): 4578-82, 2015 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-26447229

RESUMO

Plasmacytoid dendritic cells (pDCs) are professional type I IFN producers believed to promote lupus. However, questions exist about whether they function at the same level throughout the course of lupus disease. We analyzed high-purity pDCs sorted from lupus mice. Although pDCs produced a large amount of IFN-α during disease initiation, those sorted from late-stage lupus mice were found to be defective in producing IFN-α. These pDCs expressed an increased level of MHC, suggesting a functional drift to Ag presentation. We examined the potential mechanism behind the defect and identified a novel transcriptional factor, Foxj2, which repressed the expression of several genes in pDCs, but not IFN-α. Dysregulation in pDCs appears to be predisposed, because they exhibited an altered transcriptional profile before the onset of clinical signs. Our results suggest that pDCs do not function the same throughout the disease course and lose the ability to produce IFN-α in late-stage lupus mice.


Assuntos
Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Fatores de Transcrição Forkhead/imunologia , Interferon-alfa/biossíntese , Lúpus Eritematoso Sistêmico/imunologia , Animais , Células Cultivadas , Feminino , Fatores de Transcrição Forkhead/genética , Interferon-alfa/genética , Depleção Linfocítica , Camundongos , Interferência de RNA , RNA Interferente Pequeno
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