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Background Stable introns and intronic fragments make up the largest population of RNA in the oocyte nucleus of the frog Xenopus tropicalis . These stable intronic sequence RNAs (sisRNAs) persist through the onset of zygotic transcription when synchronous cell division has ended, and the developing embryo consists of approximately 8000 cells. Despite their abundance, the sequence properties and biological function of sisRNAs are just beginning to be understood. Results To characterize this population of non-coding RNA, we identified all of the sisRNAs in the X. tropicalis oocyte nucleus using published high-throughput RNA sequencing data. Our analysis revealed that sisRNAs, have an average length of ~ 360 nt, are widely expressed from genes with multiple introns, and are derived from specific regions of introns that are GC and TG rich, while CpG poor. They are enriched in introns at both ends of transcripts but preferentially at the 3′ end. The consensus binding sites of specific transcription factors such as Stat3 are enriched in sisRNAs, suggesting an association between sisRNAs and transcription factors involved in early development. Evolutionary conservation analysis of sisRNA sequences in seven vertebrate genomes indicates that sisRNAs are as conserved as other parts of introns, but much less conserved than exons. Conclusion In total, our results indicate sisRNAs are selected intron regions with distinct properties and may play a role in gene expression regulation.

Smooth muscle cells are remarkably plastic. Their reversible differentiation is required for growth and wound healing but also contributes to pathologies such as atherosclerosis and restenosis. Here we demonstrate the role of poly(ADP-ribose) polymerase 1 (PARP1) as a critical master regulator of vascular smooth muscle cells (VSMC) plasticity. A robust activation of PARP1 in VSMCs was observed in artery stenosis and atherosclerotic plaques of rodents and human. Inhibition or deletion of PARP1 suppressed the VSMC phenotype switch in vivo and in vitro. Further analysis identified myocardin and myocardin-associated serum response factor as substrates of PARP1-mediated poly(ADP-ribosyl)ation reaction. Poly(ADP-ribosyl)ation of myocardin and serum response factor dissociated the complex from CArG motif in the target promoter and then transcriptionally suppressed contractile protein expression. Moreover, we demonstrated that c-Jun mediated the stimulation of VSMC proliferation and migration by PARP1. Notably, interaction with myocardin is an important mechanism repressing c-Jun transcriptional activity in VSMCs. Poly(ADP-ribosyl)ation of myocardin and c-Jun disrupted myocardin–c-Jun interaction and abolished this repression to promote c-Jun transactivation and target gene expression, thus stimulating VSMC proliferation and migration. Our data reveal that activation of PARP1 not only suppresses contractile status but also promotes the synthetic proliferative phenotype of VSMCs, indicating a pivotal role for PARP1 in determining the phenotype of VSMCs. Targeting PARP1 may hold therapeutic potential for vascular pathologies. PARP1 regulates vascular smooth muscle cell plasticity Vascular smooth muscle cells (VSMCs) help to control blood vessel function and can change from a contractile state to a synthetic state, which is important for healing but can also lead to diseases such as atherosclerosis. This study explores how PARP1 affects this change in VSMCs. Researchers used animal models and human samples to study the role of PARP1. They found that PARP1 is highly active in VSMCs during artery injury and disease. By activating PARP1, they observed changes in VSMC behavior, such as increased or decreased cell growth and movement. PARP1 modifies proteins such as myocardin, affecting their ability to control VSMC functions. This modification disrupts the normal suppression of another protein, c-Jun, leading to more cell growth and movement. The study concludes that targeting PARP1 could be a new way to treat vascular diseases by controlling VSMC behavior. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.

Biosynthesis drives the cell volume increase during T cell activation. However, the contribution of cell volume regulation in TCR signaling during T lymphoblast formation and its underlying mechanisms remain unclear. Here we show that cell volume regulation is required for optimal T cell activation. Inhibition of VRACs (volume-regulated anion channels) and deletion of leucine-rich repeat-containing protein 8A (LRRC8A) channel components impair T cell activation and function, particularly under weak TCR stimulation. Additionally, LRRC8A has distinct influences on mRNA transcriptional profiles, indicating the prominent effects of cell volume regulation for T cell functions. Moreover, cell volume regulation via LRRC8A controls T cell-mediated antiviral immunity and shapes the TCR repertoire in the thymus. Mechanistically, LRRC8A governs stringent cell volume increase via regulated volume decrease (RVD) during T cell blast formation to keep the TCR signaling molecules at an adequate density. Together, our results show a further layer of T cell activation regulation that LRRC8A functions as a cell volume controlling “valve” to facilitate T cell activation. During the activation and migration of T cells volume changes occur in response to osmolality cues which is not fully understood. Here the authors characterize the function of volume regulated ion channels in T cells and show that these channels regulate TCR sensitivity, thymic selection and TCR repertoire.

There is an increased global outbreak of diseases caused by coronaviruses affecting respiratory tracts of birds and mammals. Recent dangerous coronaviruses are MERS-CoV, SARS-CoV, and SARS-CoV-2, causing respiratory illness and even failure of several organs. However, profound impact of coronavirus on host cells remains elusive. In this study, we analyzed transcriptome of MERS-CoV, SARS-CoV, and SARS-CoV-2 infected human lung-derived cells, and observed that infection of these coronaviruses all induced increase of retrotransposon expression with upregulation of TET genes. Upregulation of retrotransposon was also observed in SARS-CoV-2 infected human intestinal organoids. Retrotransposon upregulation may lead to increased genome instability and enhanced expression of genes with readthrough from retrotransposons. Therefore, people with higher basal level of retrotransposon such as cancer patients and aged people may have increased risk of symptomatic infection. Additionally, we show evidence supporting long-term epigenetic inheritance of retrotransposon upregulation. We also observed chimeric transcripts of retrotransposon and SARS-CoV-2 RNA for potential human genome invasion of viral fragments, with the front and the rear part of SARS-CoV-2 genome being easier to form chimeric RNA. Thus, we suggest that primers and probes for nucleic acid detection should be designed in the middle of virus genome to identify live virus with higher probability. In summary, we propose our hypothesis that coronavirus invades human cells and interacts with retrotransposon, eliciting more severe symptoms in patients with underlying diseases. In the treatment of patients with coronavirus infection, it may be necessary to pay more attention to the potential harm contributed by retrotransposon dysregulation.

Diminished ovarian reserve (DOR) is associated with heightened risk of infertility, premature menopause, and various long-term health issues. Our previous research demonstrated a correlation between prenatal propylparaben exposure and DOR in F1 mice. Here, we further reveal that the DOR phenotypes can be transgenerationally inherited in F1-F3 mice, manifested through increased follicular atresia and decreased anti-Müllerian hormone levels. Excessive apoptosis of granulosa cells is found to underlie these pathological processes. By combining diverse sequencing techniques, we identify persistent Rhobtb1 hypomethylation across multiple generations. Further exploration reveals that RhoBTB1 regulates FGF18 via ubiquitination, triggering MAPK pathway activation and subsequent granulosa cell apoptosis. Notably, similar Rhobtb1 hypomethylation patterns are observed in blood samples from DOR patients. Furthermore, intervention with a methyl-donor diet effectively ameliorates DOR phenotypes in F1-F3 offspring. These findings highlight the transgenerational effects of DOR, elucidate its underlying causes and pathogenic mechanisms, and propose potential epigenetic therapy strategies. The authors show that prenatal propylparaben exposure causes transgenerational inheritance of diminished ovarian reserve via Rhobtb1 hypomethylation, with similar patterns in patient samples. Methyl-donor diet counteracts this, suggesting therapeutic potential.

SARS-CoV-2 caused the COVID-19 pandemic. COVID-19 may elevate the risk of cognitive impairment and even cause dementia in infected individuals; it may accelerate cognitive decline in elderly patients with dementia, possibly in Alzheimer’s disease (AD) patients. However, the mechanisms underlying the interplay between AD and COVID-19 are still unclear. To investigate the underlying mechanisms and associations between AD progression and SARS-CoV-2 infection, we conducted a series of bioinformatics research into SARS-CoV-2-infected cells, COVID-19 patients, AD patients, and SARS-CoV-2-infected AD patients. We identified the common differentially expressed genes (DEGs) in COVID-19 patients, AD patients, and SARS-CoV-2-infected cells, and these DEGs are enriched in certain pathways, such as immune responses and cytokine storms. We constructed the gene interaction network with the signaling transduction module in the center and identified IRF7, STAT1, STAT2, and OAS1 as the hub genes. We also checked the correlations between several key transcription factors and the SARS-CoV-2 and COVID-19 pathway-related genes. We observed that ACE2 expression is positively correlated with IRF7 expression in AD and coronavirus infections, and interestingly, IRF7 is significantly upregulated in response to different RNA virus infections. Further snRNA-seq analysis indicates that NRGN neurons or endothelial cells may be responsible for the increase in ACE2 and IRF7 expression after SARS-CoV-2 infection. The positive correlation between ACE2 and IRF7 expressions is confirmed in the hippocampal formation (HF) of SARS-CoV-2-infected AD patients. Our findings could contribute to the investigation of the molecular mechanisms underlying the interplay between AD and COVID-19 and to the development of effective therapeutic strategies for AD patients with COVID-19.

The evolutionary model escape from adaptive conflict (EAC) posits that adaptive conflict between the old and an emerging new function within a single gene could drive the fixation of gene duplication, where each duplicate can freely optimize one of the functions. Although EAC has been suggested as a common process in functional evolution, definitive cases of neofunctionalization under EAC are lacking, and the molecular mechanisms leading to functional innovation are not well-understood. We report here clear experimental evidence for EAC-driven evolution of type III antifreeze protein gene from an old sialic acid synthase ( SAS ) gene in an Antarctic zoarcid fish. We found that an SAS gene, having both sialic acid synthase and rudimentary ice-binding activities, became duplicated. In one duplicate, the N-terminal SAS domain was deleted and replaced with a nascent signal peptide, removing pleiotropic structural conflict between SAS and ice-binding functions and allowing rapid optimization of the C-terminal domain to become a secreted protein capable of noncolligative freezing-point depression. This study reveals how minor functionalities in an old gene can be transformed into a distinct survival protein and provides insights into how gene duplicates facing presumed identical selection and mutation pressures at birth could take divergent evolutionary paths.

DNA methylation (DNAm) has been implicated in acute coronary syndrome (ACS), but the causality remains unclear in cross-sectional studies. Here, we conduct a prospective epigenome-wide association study of incident ACS in two Chinese cohorts (discovery: 751 nested case-control pairs; replication: 476 nested case-control pairs). We identified and validated 26 differentially methylated positions (DMPs, false discovery rate [ FDR ] <0.05), including three mapped to known cardiovascular disease genes ( PRKCZ , PRDM16 , EHBP1L1 ) and four with causal evidence from Mendelian randomization ( PRKCZ , TRIM27 , EMC2 , EHBP1L1 ). Two hypomethylated DMPs were negatively correlated with the expression in blood of their mapped genes ( PIGG and EHBP1L1 ), which were further found to overexpress in leukocytes and/or atheroma plaques. Finally, our DMPs could substantially improve the prediction of ACS over traditional risk factors and polygenic scores. These findings demonstrate the importance of DNAm in the pathogenesis of ACS and highlight DNAm as potential predictive biomarkers and treatment targets. Here, the authors identify key DNA methylation sites associated with incident acute coronary syndrome (ACS), improving ACS prediction and highlighting potential biomarkers and therapeutic targets for ACS.

The occurrence of gene duplication/amplification (GDA) provide potential material for adaptive evolution with environmental stress. Several molecular models have been proposed to explain GDA, recombination via short stretches of sequence similarity plays a crucial role. By screening genomes for such events, we propose a “SRS (short repeated sequence) *N + unit + SRS*N” amplified unit under USCE (unequal sister-chromatid exchange) for tandem amplification mediated by SRS with different repeat numbers in eukaryotes. The amplified units identified from 2131 well-organized amplification events that generate multi gene/element copy amplified with subsequent adaptive evolution in the respective species. Genomic data we analyzed showed dynamic changes among related species or subspecies or plants from different ecotypes/strains. This study clarifies the characteristics of variable copy number SRS on both sides of amplified unit under USCE mechanism, to explain well-organized gene tandem amplification under environmental stress mediated by SRS in all eukaryotes.