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"Frost, Jennifer"
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Regulation of transposable elements by DNA modifications
Maintenance of genome stability requires control over the expression of transposable elements (TEs), whose activity can have substantial deleterious effects on the host. Chemical modification of DNA is a commonly used strategy to achieve this, and it has long been argued that the emergence of 5-methylcytosine (5mC) in many species was driven by the requirement to silence TEs. Potential roles in TE regulation have also been suggested for other DNA modifications, such as N6-methyladenine and oxidation derivatives of 5mC, although the underlying mechanistic relationships are poorly understood. Here, we discuss current evidence implicating DNA modifications and DNA-modifying enzymes in TE regulation across different species.Transposable elements (TEs) need to be tightly regulated in genomes to prevent the detrimental consequences of transposition. In this Review, Deniz, Frost and Branco discuss how DNA methylation dynamics play a central role in the multilayered epigenetic mechanisms regulating TEs. Beyond roles for 5-methylcytosine (5mC), they discuss TET-mediated oxidation products of 5mC, as well as ongoing debates about the functional relevance of adenine methylation.
Journal Article
The Importance of Imprinting in the Human Placenta
As a field of study, genomic imprinting has grown rapidly in the last 20 years, with a growing figure of around 100 imprinted genes known in the mouse and approximately 50 in the human. The imprinted expression of genes may be transient and highly tissue-specific, and there are potentially hundreds of other, as yet undiscovered, imprinted transcripts. The placenta is notable amongst mammalian organs for its high and prolific expression of imprinted genes. This review discusses the development of the human placenta and focuses on the function of imprinting in this organ. Imprinting is potentially a mechanism to balance parental resource allocation and it plays an important role in growth. The placenta, as the interface between mother and fetus, is central to prenatal growth control. The expression of genes subject to parental allelic expression bias has, over the years, been shown to be essential for the normal development and physiology of the placenta. In this review we also discuss the significance of genes that lack conservation of imprinting between mice and humans, genes whose imprinted expression is often placental-specific. Finally, we illustrate the importance of imprinting in the postnatal human in terms of several human imprinting disorders, with consideration of the brain as a key organ for imprinted gene expression after birth.
Journal Article
الملك لير
\"الملك لير\" من مسرحيات \"شكسبير\" الرائعة وتتميز بتقديم خلفية تاريخية عن أحداث المسرحية ليتعرف القارئ على الحقبة الزمنية التي وقعت فيها تلك الأحداث التعريف بشخصيات المسرحية وبأهم سماتهم تقديم أحداث المسرحية بأسلوب سهل ومبسط يناسب جميع الأعمار مع استشهادات من النص الذي كتبه \"شكسبير\"مجموعة من اللوحات الفنية والصور الرائعة المعبرة التي تجعل القارئ يعايش الأحداث.
Book
Insights into plant regeneration: cellular pathways and DNA methylation dynamics
Plants, known for their immobility, employ various mechanisms against stress and damage. A prominent feature is the formation of callus tissue—a cellular growth phenomenon that remains insufficiently explored, despite its distinctive cellular plasticity compared to vertebrates. Callus formation involves dedifferentiated cells, with a subset attaining pluripotency. Calluses exhibit an extraordinary capacity to reinitiate cellular division and undergo structural transformations, generating de novo shoots and roots, thereby developing into regenerated plants—a testament to the heightened developmental plasticity inherent in plants. In this way, plant regeneration through clonal propagation is a widely employed technique for vegetative reproduction. Thus, exploration of the biological components involved in regaining pluripotency contributes to the foundation upon which methods of somatic plant propagation can be advanced. This review provides an overview of the cellular pathway involved in callus and subsequent de novo shoot formation from already differentiated plant tissue, highlighting key genes critical to this process. In addition, it explores the intricate realm of epigenetic regulatory processes, emphasizing the nuanced dynamics of DNA methylation that contribute to plant regeneration. Finally, we briefly discuss somaclonal variation, examining its relation to DNA methylation, and investigating the heritability of epigenomic changes in crops.
Journal Article
أنطونيو وكليوباترا
\"أنطونيو وكليوباترا\" من مسرحيات \"شكسبير\" الرائعة وتتميز بتقديم خلفية تاريخية عن أحداث المسرحية ليتعرف القارئ على الحقبة الزمنية التي وقعت فيها تلك الأحداث التعريف بشخصيات المسرحية وبأهم سماتهم تقديم أحداث المسرحية بأسلوب سهل ومبسط يناسب جميع الأعمار مع استشهادات من النص الذي كتبه \"شكسبير\"مجموعة من اللوحات الفنية والصور الرائعة المعبرة التي تجعل القارئ يعايش الأحداث.
Book
Young Adults' Contraceptive Knowledge, Norms and Attitudes: Associations with Risk Of Unintended Pregnancy
CONTEXT: Women aged 18–29 hove higher rates of unintended pregnancy than any other age-group. Information is needed to understand what characteristics are associated with risky contraceptive use practices among this population and to develop new strategies for reducing these women's risk of unintended pregnancy. METHODS: Data related to unintended pregnancy risk were collected from a nationally representative sample of 1,800 unmarried women and men aged 18–29 surveyed by telephone in 2009. Among those at risk of unintended pregnancy, multiple logistic regression was used to assess associations between contraceptive knowledge, norms and attitudes and selected risky contraceptive behaviors. RESULTS: More than half of young men and a quarter of young women received low scores on contraceptive knowledge, and six in 10 underestimated the effectiveness of oral contraceptives. Among women, for each correct response on a contraceptive knowledge scale, the odds of expecting to have unprotected sex in the next three months decreased by 9%, of currently using a hormonal or long-acting reversible method increased by 17%, and of using no method decreased by 17%. Fear of side effects, norms and attitudes that favor nonmarital pregnancy or undervalue the importance of contraception, pregnancy ambivalence and mistrust of government's role in promoting contraception were also associated with one or more risky contraceptive use behaviors. CONCLUSIONS: Programs to increase young adults' knowledge about contraceptive methods and use are urgently needed. Given the demonstrated link between method knowledge and contraceptive behaviors, such programs may be useful in addressing risky behavior in this population.
Journal Article
eIF2B activator prevents neurological defects caused by a chronic integrated stress response
The integrated stress response (ISR) attenuates the rate of protein synthesis while inducing expression of stress proteins in cells. Various insults activate kinases that phosphorylate the GTPase eIF2 leading to inhibition of its exchange factor eIF2B. Vanishing White Matter (VWM) is a neurological disease caused by eIF2B mutations that, like phosphorylated eIF2, reduce its activity. We show that introduction of a human VWM mutation into mice leads to persistent ISR induction in the central nervous system. ISR activation precedes myelin loss and development of motor deficits. Remarkably, long-term treatment with a small molecule eIF2B activator, 2BAct, prevents all measures of pathology and normalizes the transcriptome and proteome of VWM mice. 2BAct stimulates the remaining activity of mutant eIF2B complex in vivo, abrogating the maladaptive stress response. Thus, 2BAct-like molecules may provide a promising therapeutic approach for VWM and provide relief from chronic ISR induction in a variety of disease contexts. Cells must be able to respond to their changing environment in order to survive. When cells encounter particularly unfavorable conditions, they often react by activating a so-called ‘stress’ response. A group of proteins collectively known as eIF2B helps to regulate this response. In a severe neurological condition called Vanishing White Matter (VWM), the genes that produce the eIF2B proteins contain mutations that make eIF2B less active. As a result, certain cells in people with VWM are always stressed. Six years ago, researchers discovered a molecule that boosts the activity of eIF2B. In 2018, they found that it also works on various mutant forms of eIF2B found in VWM. The molecule had so far only been tested in biochemical laboratory experiments. Now, Wong et al. – including some of the researchers involved in the 2018 study – have tested whether an improved version of the molecule treats VWM in mice. The trial treatment successfully halted all signs of the disease in the mice. The molecule blunted the persistent stress response of the cells in the brain and spinal cord, primarily in a cell type that is severely affected by the human form of VWM. Cells in other parts of the body were spared. Overall, the results of the experiments suggest that an eIF2B activator may prove to be an effective treatment for VWM in humans. It could similarly be used to treat other conditions that activate this abnormal cell stress response. The molecule Wong et al. used is not suitable for use in humans, so work is continuing to find a suitable variant.
Journal Article
Regulation of human trophoblast gene expression by endogenous retroviruses
The placenta is a fast-evolving organ with large morphological and histological differences across eutherians, but the genetic changes driving placental evolution have not been fully elucidated. Transposable elements, through their capacity to quickly generate genetic variation and affect host gene regulation, may have helped to define species-specific trophoblast gene expression programs. Here we assess the contribution of transposable elements to human trophoblast gene expression as enhancers or promoters. Using epigenomic data from primary human trophoblast and trophoblast stem-cell lines, we identified multiple endogenous retrovirus families with regulatory potential that lie close to genes with preferential expression in trophoblast. These largely primate-specific elements are associated with inter-species gene expression differences and are bound by transcription factors with key roles in placental development. Using genetic editing, we demonstrate that several elements act as transcriptional enhancers of important placental genes, such as
CSF1R
and
PSG5
. We also identify an LTR10A element that regulates
ENG
expression, affecting secretion of soluble endoglin, with potential implications for preeclampsia. Our data show that transposons have made important contributions to human trophoblast gene regulation, and suggest that their activity may affect pregnancy outcomes.
Here the authors investigate the contribution of transposable elements to regulation of gene expression in human trophoblasts. Amongst other examples, they identify an LTR10A element with potential implications for preeclampsia.
Journal Article