In Silico Identification of miRNA–lncRNA Interactions in Male Reproductive Disorder Associated with COVID-19 Infection

Coronavirus disease 2019 (COVID-19), a global pandemic, is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Angiotensin-converting enzyme 2 (ACE2) is the receptor for SARS-CoV-2 and transmembrane serine protease 2 (TMPRSS2) facilitates ACE2-mediated virus entry. Moreover, the expression of ACE2 in the testes of infertile men is higher than normal, which indicates that infertile men may be susceptible to be infected and SARS-CoV-2 may cause reproductive disorder through the pathway induced by ACE2 and TMPRSS2. Little is known about the pathway regulation of ACE2 and TMPRSS2 expression in male reproductive disorder. Since the regulation of gene expression is mediated by microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) at the post-transcriptional level, the aim of this study was to analyze the dysregulated miRNA–lncRNA interactions of ACE2 and TMPRSS2 in male reproductive disorder. Using bioinformatics analysis, we speculate that the predicted miRNAs including miR-125a-5p, miR-125b-5p, miR-574-5p, and miR-936 as regulators of ACE2 and miR-204-5p as a modulator of TMPRSS2 are associated with male infertility. The lncRNAs with a tissue-specific expression for testis including GRM7-AS3, ARHGAP26-AS1, BSN-AS1, KRBOX1-AS1, CACNA1C-IT3, AC012361.1, FGF14-IT1, AC012494.1, and GS1-24F4.2 were predicted. The identified miRNAs and lncRNAs are proposed as potential biomarkers to study the possible association between COVID-19 and male infertility. This study encourages further studies of miRNA–lncRNA interactions to explain the molecular mechanisms of male infertility in COVID-19 patients.

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Sex-Specific MicroRNAs in Neurovascular Units in Ischemic Stroke

International Journal of Molecular Sciences ◽

10.3390/ijms222111888 ◽

2021 ◽

Vol 22 (21) ◽

pp. 11888

Author(s):

Barend W. Florijn ◽

Roel Bijkerk ◽

Nyika D. Kruyt ◽

Anton Jan van Zonneveld ◽

Marieke J. H. Wermer

Keyword(s):

Ischemic Stroke ◽

X Chromosome ◽

Cellular Response ◽

Molecular Mechanisms ◽

Regulation Of Gene Expression ◽

Transcriptional Level ◽

Cell Type ◽

Stroke Incidence ◽

Secondary Damage ◽

Mechanistic Understanding

Accumulating evidence pinpoints sex differences in stroke incidence, etiology and outcome. Therefore, more understanding of the sex-specific mechanisms that lead to ischemic stroke and aggravation of secondary damage after stroke is needed. Our current mechanistic understanding of cerebral ischemia states that endothelial quiescence in neurovascular units (NVUs) is a major physiological parameter affecting the cellular response to neuron, astrocyte and vascular smooth muscle cell (VSMC) injury. Although a hallmark of the response to injury in these cells is transcriptional activation, noncoding RNAs such as microRNAs exhibit cell-type and context dependent regulation of gene expression at the post-transcriptional level. This review assesses whether sex-specific microRNA expression (either derived from X-chromosome loci following incomplete X-chromosome inactivation or regulated by estrogen in their biogenesis) in these cells controls NVU quiescence, and as such, could differentiate stroke pathophysiology in women compared to men. Their adverse expression was found to decrease tight junction affinity in endothelial cells and activate VSMC proliferation, while their regulation of paracrine astrocyte signaling was shown to neutralize sex-specific apoptotic pathways in neurons. As such, these microRNAs have cell type-specific functions in astrocytes and vascular cells which act on one another, thereby affecting the cell viability of neurons. Furthermore, these microRNAs display actual and potential clinical implications as diagnostic and prognostic biomarkers in ischemic stroke and in predicting therapeutic response to antiplatelet therapy. In conclusion, this review improves the current mechanistic understanding of the molecular mechanisms leading to ischemic stroke in women and highlights the clinical promise of sex-specific microRNAs as novel diagnostic biomarkers for (silent) ischemic stroke.

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Decoding resistant hypertension signalling pathways

Clinical Science ◽

10.1042/cs20171398 ◽

2017 ◽

Vol 131 (23) ◽

pp. 2813-2834 ◽

Cited By ~ 4

Author(s):

Ricardo Cambraia Parreira ◽

Leandro Heleno Guimarães Lacerda ◽

Rebecca Vasconcellos ◽

Swiany Silveira Lima ◽

Anderson Kenedy Santos ◽

...

Keyword(s):

Resistant Hypertension ◽

Molecular Mechanisms ◽

Regulation Of Gene Expression ◽

Signalling Pathways ◽

Transcriptional Level ◽

Cardiovascular Damage ◽

Current State ◽

Cardiovascular Morbidity And Mortality ◽

Non Coding Rnas ◽

Therapeutic Tools

Resistant hypertension (RH) is a clinical condition in which the hypertensive patient has become resistant to drug therapy and is often associated with increased cardiovascular morbidity and mortality. Several signalling pathways have been studied and related to the development and progression of RH: modulation of sympathetic activity by leptin and aldosterone, primary aldosteronism, arterial stiffness, endothelial dysfunction and variations in the renin–angiotensin–aldosterone system (RAAS). miRNAs comprise a family of small non-coding RNAs that participate in the regulation of gene expression at post-transcriptional level. miRNAs are involved in the development of both cardiovascular damage and hypertension. Little is known of the molecular mechanisms that lead to development and progression of this condition. This review aims to cover the potential roles of miRNAs in the mechanisms associated with the development and consequences of RH, and explore the current state of the art of diagnostic and therapeutic tools based on miRNA approaches.

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Prm2 deficiency triggers a Reactive Oxygen Species (ROS)-mediated destruction cascade during epididymal sperm maturation in mice

10.1101/2020.05.05.075929 ◽

2020 ◽

Author(s):

Simon Schneider ◽

Farhad Shakeri ◽

Christian Trötschel ◽

Lena Arévalo ◽

Alexander Kruse ◽

...

Keyword(s):

Oxidative Stress ◽

Male Infertility ◽

Molecular Mechanisms ◽

Sperm Maturation ◽

Preimplantation Embryos ◽

Sperm Function ◽

Epididymal Sperm ◽

Small Proteins ◽

Infertile Men ◽

New Treatment

AbstractProtamines are the safeguards of the paternal sperm genome. They replace most of the histones during spermiogenesis, resulting in DNA hypercondensation, thereby protecting its genome from environmental noxa. Impaired protamination has been linked to male infertility in mice and humans in many studies. Apart from impaired DNA integrity, protamine-deficient human and murine sperm show multiple secondary effects, including decreased motility and aberrant head morphology. In this study, we use a Prm2-deficient mouse model in combination with label-free quantitative proteomics to decipher the underlying molecular processes of these effects. We show that loss of the sperm’s antioxidant capacity, indicated by downregulation of key proteins like SOD1 and PRDX5, ultimately initiates an oxidative stress-mediated destruction cascade during epididymal sperm maturation. This is confirmed by an increased level of 8-OHdG in epididymal sperm, a biomarker for oxidative stress-mediated DNA damage. Prm2-deficient testicular sperm are not affected and initiate the proper development of blastocyst stage preimplantation embryos in vitro upon intracytoplasmic sperm injection (ICSI) into oocytes. Our results provide new insight into the role of Prm2 and its downstream molecular effects on sperm function and present an important contribution to the investigation of new treatment regimens for infertile men with impaired protamination.Significance statementSexual reproduction requires the successful fertilization of female eggs by male sperm. The generation of functional sperm is a complex, multi-step differentiation process known as spermatogenesis that takes places in the male testis. One important step for physiological sperm function is the incorporation of small proteins, known as protamines into the DNA. Defects within this process are common causes of male infertility. However, the underlying molecular mechanisms still remain largely unknown, thus preventing targeted therapies. Here, we identify the molecular cascade being initiated in protamine-deficient murine sperm that ultimately impedes fertilization. Our findings have broad implications for the development of new treatment options for infertile men with faulty protamination that seek medical advice.

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Cell-specific expression of ENACα gene by FOXA1 in the glucocorticoid receptor pathway

International Journal of Immunopathology and Pharmacology ◽

10.1177/2058738420946192 ◽

2020 ◽

Vol 34 ◽

pp. 205873842094619 ◽

Cited By ~ 1

Author(s):

Young Sun Chung ◽

Hong Lan Jin ◽

Kwang Won Jeong

Keyword(s):

Gene Expression ◽

Glucocorticoid Receptor ◽

Molecular Mechanisms ◽

Regulation Of Gene Expression ◽

A549 Cells ◽

Rna Seq ◽

Cell Type ◽

Specific Expression ◽

Cell Type Specific ◽

Specific Regulation

Introduction: The glucocorticoid receptor (GR) is one of the most widely studied ligand-dependent nuclear receptors. The combination of transcriptional regulatory factors required for the expression of individual genes targeted by GR varies across cell types; however, the mechanisms underlying this cell type–specific regulation of gene expression are not yet clear. Methods: Here, we investigated genes regulated by GR in two different cell lines, A549 and ARPE-19, and examined how gene expression varied according to the effect of pioneer factors using RNA-seq and RT-qPCR. Results: Our RNA-seq results identified 19 and 63 genes regulated by GR that are ARPE-19-specific and A549-specific, respectively, suggesting that GR induces the expression of different sets of genes in a cell type–specific manner. RT-qPCR confirmed that the epithelial sodium channel ( ENACα) gene is an ARPE-19 cell-specific GR target gene, whereas the FK506 binding protein 5 ( FKBP5) gene was A549 cell-specific. There was a significant decrease in ENACα expression in FOXA1-deficient ARPE-19 cells, suggesting that FOXA1 might function as a pioneer factor enabling the selective expression of ENACα in ARPE-19 cells but not in A549 cells. Conclusion: These findings indicate that ENACα expression in ARPE-19 cells is regulated by FOXA1 and provide insights into the molecular mechanisms of cell type–specific expression of GR-regulated genes.

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The influence of Robertsonian translocations on semen parameters

Nauchno-prakticheskii zhurnal «Medicinskaia genetika» ◽

10.25557/2073-7998.2020.03.87-88 ◽

2020 ◽

pp. 87-88

Author(s):

М.В. Андреева ◽

М.И. Штаут ◽

Т.М. Сорокина ◽

Л.Ф. Курило ◽

В.Б. Черных

Keyword(s):

Male Infertility ◽

Semen Parameters ◽

Meiotic Arrest ◽

Robertsonian Translocations ◽

Prophase I ◽

Infertile Men ◽

Fertility Problems ◽

Spermatogenesis Impairment

Обследованы 19 мужчин с нарушением фертильности, носителей транслокаций rob(13;14) и rob(13;15). Показано, что нарушение репродуктивной функции обусловлено блоком сперматогенеза в профазе I мейоза, приводящего к азооспермии или олигоастенотератозооспермии и мужскому бесплодию. We examined 19 infertile men, carriers of translocations rob (13;14) and rob (13;15). We assume that fertility problems are resulted from spermatogenesis impairment because of meiotic arrest at prophase I stages, that leads to azoospermia or oligoastenoteratozoospermia and male infertility.

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Lighting a path: genetic studies pinpoint neurodevelopmental mechanisms in autism and related disorders

Dialogues in Clinical Neuroscience ◽

10.31887/10.31887/dcns.2012.14.3/mpescosolido ◽

2012 ◽

Vol 14 (3) ◽

pp. 239-252

Keyword(s):

Molecular Mechanisms ◽

Protein Localization ◽

Regulation Of Gene Expression ◽

Neuronal Cell ◽

Mrna Splicing ◽

Genetic Mutations ◽

Scaffolding Proteins ◽

Molecular Processes ◽

Genetic Studies ◽

Novel Treatments

In this review, we outline critical molecular processes that have been implicated by discovery of genetic mutations in autism. These mechanisms need to be mapped onto the neurodevelopment step(s) gone awry that may be associated with cause in autism. Molecular mechanisms include: (i) regulation of gene expression; (ii) pre-mRNA splicing; (iii) protein localization, translation, and turnover; (iv) synaptic transmission; (v) cell signaling; (vi) the functions of cytoskeletal and scaffolding proteins; and (vii) the function of neuronal cell adhesion molecules. While the molecular mechanisms appear broad, they may converge on only one of a few steps during neurodevelopment that perturbs the structure, function, and/or plasticity of neuronal circuitry. While there are many genetic mutations involved, novel treatments may need to target only one of few developmental mechanisms.

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Regulation of gene expression during spermatogenesis at transcriptional level

Hereditas (Beijing) ◽

10.3724/sp.j.1005.2011.01300 ◽

2011 ◽

Vol 33 (12) ◽

pp. 1300-1307

Author(s):

Xiu-Jun ZHANG ◽

Mei-Ling LIU ◽

Meng-Chun JIA

Keyword(s):

Gene Expression ◽

Regulation Of Gene Expression ◽

Transcriptional Level

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Idiopathic Infertility as a Feature of Genome Instability

Life ◽

10.3390/life11070628 ◽

2021 ◽

Vol 11 (7) ◽

pp. 628

Author(s):

Agrita Puzuka ◽

Baiba Alksere ◽

Linda Gailite ◽

Juris Erenpreiss

Keyword(s):

Life Expectancy ◽

Male Infertility ◽

Genome Instability ◽

Repair System ◽

Environmental Aspects ◽

Strand Breaks ◽

Testicular Dysfunction ◽

Infertile Men ◽

Dna Strand ◽

Dynamic Mutations

Genome instability may play a role in severe cases of male infertility, with disrupted spermatogenesis being just one manifestation of decreased general health and increased morbidity. Here, we review the data on the association of male infertility with genetic, epigenetic, and environmental alterations, the causes and consequences, and the methods for assessment of genome instability. Male infertility research has provided evidence that spermatogenic defects are often not limited to testicular dysfunction. An increased incidence of urogenital disorders and several types of cancer, as well as overall reduced health (manifested by decreased life expectancy and increased morbidity) have been reported in infertile men. The pathophysiological link between decreased life expectancy and male infertility supports the notion of male infertility being a systemic rather than an isolated condition. It is driven by the accumulation of DNA strand breaks and premature cellular senescence. We have presented extensive data supporting the notion that genome instability can lead to severe male infertility termed “idiopathic oligo-astheno-teratozoospermia.” We have detailed that genome instability in men with oligo-astheno-teratozoospermia (OAT) might depend on several genetic and epigenetic factors such as chromosomal heterogeneity, aneuploidy, micronucleation, dynamic mutations, RT, PIWI/piRNA regulatory pathway, pathogenic allelic variants in repair system genes, DNA methylation, environmental aspects, and lifestyle factors.

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The transcription factor SlHY5 regulates the ripening of tomato fruit at both the transcriptional and translational levels

Horticulture Research ◽

10.1038/s41438-021-00523-0 ◽

2021 ◽

Vol 8 (1) ◽

Author(s):

Weihao Wang ◽

Peiwen Wang ◽

Xiaojing Li ◽

Yuying Wang ◽

Shiping Tian ◽

...

Keyword(s):

Fruit Ripening ◽

Nutritional Quality ◽

Ribosomal Proteins ◽

Anthocyanin Biosynthesis ◽

Tomato Fruit ◽

Critical Role ◽

Regulation Of Gene Expression ◽

Protein Translation ◽

Transcriptional Level ◽

Translation Efficiency

AbstractLight plays a critical role in plant growth and development, but the mechanisms through which light regulates fruit ripening and nutritional quality in horticultural crops remain largely unknown. Here, we found that ELONGATED HYPOCOTYL 5 (HY5), a master regulator in the light signaling pathway, is required for normal fruit ripening in tomato (Solanum lycopersicum). Loss of function of tomato HY5 (SlHY5) impairs pigment accumulation and ethylene biosynthesis. Transcriptome profiling identified 2948 differentially expressed genes, which included 1424 downregulated and 1524 upregulated genes, in the Slhy5 mutants. In addition, genes involved in carotenoid and anthocyanin biosynthesis and ethylene signaling were revealed as direct targets of SlHY5 by chromatin immunoprecipitation. Surprisingly, the expression of a large proportion of genes encoding ribosomal proteins was downregulated in the Slhy5 mutants, and this downregulation pattern was accompanied by a decrease in the abundance of ribosomal proteins. Further analysis demonstrated that SlHY5 affected the translation efficiency of numerous ripening-related genes. These data indicate that SlHY5 regulates fruit ripening both at the transcriptional level by targeting specific molecular pathways and at the translational level by affecting the protein translation machinery. Our findings unravel the regulatory mechanisms of SlHY5 in controlling fruit ripening and nutritional quality and uncover the multifaceted regulation of gene expression by transcription factors.

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Desiccation Tolerance as the Basis of Long-Term Seed Viability

International Journal of Molecular Sciences ◽

10.3390/ijms22010101 ◽

2020 ◽

Vol 22 (1) ◽

pp. 101

Author(s):

Galina Smolikova ◽

Tatiana Leonova ◽

Natalia Vashurina ◽

Andrej Frolov ◽

Sergei Medvedev

Keyword(s):

Desiccation Tolerance ◽

Vascular Plants ◽

Molecular Mechanisms ◽

Regulation Of Gene Expression ◽

Seed Viability ◽

Late Embryogenesis Abundant ◽

Maturation Stage ◽

Terrestrial Plants ◽

Complex Anatomy ◽

Orthodox Seeds

Desiccation tolerance appeared as the key adaptation feature of photoautotrophic organisms for survival in terrestrial habitats. During the further evolution, vascular plants developed complex anatomy structures and molecular mechanisms to maintain the hydrated state of cell environment and sustain dehydration. However, the role of the genes encoding the mechanisms behind this adaptive feature of terrestrial plants changed with their evolution. Thus, in higher vascular plants it is restricted to protection of spores, seeds and pollen from dehydration, whereas the mature vegetative stages became sensitive to desiccation. During maturation, orthodox seeds lose up to 95% of water and successfully enter dormancy. This feature allows seeds maintaining their viability even under strongly fluctuating environmental conditions. The mechanisms behind the desiccation tolerance are activated at the late seed maturation stage and are associated with the accumulation of late embryogenesis abundant (LEA) proteins, small heat shock proteins (sHSP), non-reducing oligosaccharides, and antioxidants of different chemical nature. The main regulators of maturation and desiccation tolerance are abscisic acid and protein DOG1, which control the network of transcription factors, represented by LEC1, LEC2, FUS3, ABI3, ABI5, AGL67, PLATZ1, PLATZ2. This network is complemented by epigenetic regulation of gene expression via methylation of DNA, post-translational modifications of histones and chromatin remodeling. These fine regulatory mechanisms allow orthodox seeds maintaining desiccation tolerance during the whole period of germination up to the stage of radicle protrusion. This time point, in which seeds lose desiccation tolerance, is critical for the whole process of seed development.

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