Biology subjects

Chen, C.

Publications and source records attributed to Chen, C..

At least 361 records · Page 20Linked to original sources

bioRxiv2023

ADNP Modulates SINE B2-Derived CTCF-Binding Sites during Blastocyst Formation in Mouse

During early embryo development, the nuclear factor CTCF plays a vital role in organizing chromatin structure and regulating transcription. Recent studies have examined the establishment of nucleosome profiles around the CTCF motif sites shortly after fertilization. However, the kinetics of CTCF chromatin occupation in pre-implantation embryos have remained unclear. In this study, we utilized CUT&RUN technology to investigate CTCF occupancy in mouse pre-implantation development. Our findings revealed that CTCF begins binding to the genome prior to zygotic genome activation (ZGA), with a preference for CTCF anchored chromatin loops. Although the majority of CTCF occupancy is consistently maintained, we identified a specific set of binding sites enriched in the mouse-specific short-interspersed element (SINE) family B2, which are restricted to the cleavage stages. Notably, our data suggested that the neuroprotective protein ADNP may counteract the stable association of CTCF at SINE B2-derived CTCF-binding sites.

developmental biology↗

bioRxiv2023

A mitochondria-regulated p53-CCF circuit integrates genome integrity with inflammation

Genomic instability and inflammation are distinct hallmarks of aging, but the connection between them is poorly understood. Understanding their interrelationship will help unravel new mechanisms and therapeutic targets of aging and age-associated diseases. Here we report a novel mechanism directly linking genomic instability and inflammation in senescent cells through a mitochondria-regulated molecular circuit driven by p53 and cytoplasmic chromatin fragments (CCF). We show, through activation or inactivation of p53 by genetic and pharmacologic approaches, that p53 suppresses CCF accumulation and the downstream inflammatory senescence-associated secretory phenotype (SASP), without affecting cell cycle arrest. p53 activation suppressed CCF formation by promoting DNA repair, and this is reflected in maintenance of genomic integrity, particularly in subtelomeric regions, as shown by single cell genome resequencing. Activation of p53 in aged mice by pharmacological inhibition of MDM2 reversed signatures of aging, including age- and senescence-associated transcriptomic signatures of inflammation and age-associated accumulation of monocytes and macrophages in liver. Remarkably, mitochondria in senescent cells suppressed p53 activity by promoting CCF formation and thereby restricting ATM-dependent nuclear DNA damage signaling. These data provide evidence for a mitochondria-regulated p53 signaling circuit in senescent cells that controls DNA repair, genome integrity, and senescence- and age-associated inflammation. This pathway is immunomodulatory in mice and a potential target for healthy aging interventions by small molecules already shown to activate p53.

cell biology↗

bioRxiv2023

A novel antagonist of the CCL5/CCR5 axis suppresses the tumor growth and metastasis of triple-negative breast cancer by CCR5-YAP1 regulation.

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer (BC) with a high mortality rate, and few effective therapeutic strategies are available. CCL5/CCR5 is an appealing immunotherapeutic target for TNBC. However, its signaling mechanism is poorly understood and its direct antagonists have not been reported. Here, we developed a high-throughput screening (HTS) assay for discovering its antagonists. Verteporfin was identified as a more selective and potent antagonist than the known CCR5 antagonist maraviroc. Without photodynamic therapy, verteporfin demonstrated significant inhibition on TNBC tumor growth through immune regulation, remarkable suppression of lung metastasis by cell-intrinsic mechanism, and a significant extension of overall survival in vivo. Mechanistically, CCR5 was found to be essential for expression of the key hippo effector YAP1. It promoted YAP1 transcription via HIF-1 and exerted further control over the migration of CD8+ T, NK, and MDSC immune cells through chemokines CXCL16 and CXCL8 which were identified from RNA-seq. Moreover, the CCR5-YAP1 axis played a vital role in promoting metastasis by modulating {beta}-catenin and core epithelial-mesenchymal transition transcription factors ZEB1 and ZEB2. It is noteworthy that the regulatory relationship between CCR5 and YAP1 was observed across various BC subtypes, TNBC patients, and showed potential relevance in fifteen additional cancer types. Overall, this study introduced an easy-to-use HTS assay that streamlines the discovery of CCL5/CCR5 axis antagonists. Verteporfin was identified as a specific molecular probe of this axis with great potentials as a therapeutic agent for treating sixteen malignant diseases characterized by heightened CCR5 and YAP1 levels.

cancer biology↗

bioRxiv2023

In situ observation and range extension of the first monoplacophoran Neopilina galatheae

Monoplacophoran molluscs have been dubbed "living fossils" due to their absence in the fossil record for about 375 million years, until Neopilina galatheae Lemche, 1957 was trawled off Costa Rica in 1952. Since then, over 35 species of living monoplacophorans have been discovered. Nevertheless, in situ observations of these rare deep-sea animals remain scant. Here, we observed and collected an intact specimen of N. galatheae using a remotely operated vehicle from 2460 m deep on the Eastern Galapagos Spreading Center. The animal was found attached to the glassy surface of solidified basalt lava flow, and no feeding trails were found near the animal. Such hard substrate is in contrast with previous records that were trawled on sand and mud, suggesting Neopilina can be found on a wide range of substrates. This is the first time this species was collected since 1959, and represents a southeast range extension of about 1000 km for the species.

zoology↗

bioRxiv2023

Study on genetic differentiation of Schistosome japonicum intermediate hosts Oncomelania hupensis robertsoni in hilly regions of China: using the complete mitochondrial genome

ObjectiveOncomelania hupensis robertsoni is the only intermediate host of Schistosoma japonicum in western China, its genetic differentiation directly impacts the susceptibility of Schistosoma japonicum. This study aimed to sequence the complete mitochondrial genome of Oncomelania hupensis robertsoni Yunnan strain and analyze the genetic differentiation of Oncomelania hupensis robertsoni in hilly regions of China. MethodsSamples were from 14 administrative villages in Yunnan Province of China, with 30 Oncomelania hupensis per village, and the complete mitochondrial genome was sequenced. Additional, we retrieved 14 other region Oncomelania hupensis of complete mitochondrial sequences from GenBank, and a comprehensive analysis of the genetic differentiation of Oncomelania hupensis robertsoni was conducted by constructing phylogenetic trees, calculating genetic distances, and analyzing homogeneity. ResultsA total of 26 complete mitochondrial sequences were determined. The length of genome ranged from 15,181 to 15,187 bp, and the base composition of the genome was A+T (67.5%) and G+C content (32.5%). This genome encoded 37 genes, including 13 protein-coding genes, 2 rRNA genes, 22 tRNA genes and a non-coding region rich in A+T. Using the Philippines genotypes as outgroup, the phylogenetic trees and homology analysis confirmed the existence of two distinct phylogroups, Oncomelania hupensis robertsoni and the remaining 9 provincial genotypes. Oncomelania hupensis robertsoni is subdivided into Oncomelania hupensis robertsoni Yunnan strain and Sichuan strain, with a genetic distance of 0.0834. Oncomelania hupensis robertsoni Yunnan strain is subdivided into two subbranches, "Yunnan North" and "Yunnan South", with a genetic distance of 0.0216, and the samples exhibited over 97% homology. ConclusionOncomelania hupensis robertsoni Yunnan strain exhibits a higher level of genetic homology and clear north-south differentiation, the distribution characteristics were closely associated with watershed distribution. This work reported the first mitochondrial genome of Oncomelania hupensis robertsoni Yunnan strain, which could be used as an important reference genome for Oncomelania hupensis, and also provide a theoretical basis for explaining the distribution pattern of Oncomelania hupensis robertsoni and control of schistosomiasis. Author SummaryOncomelania hupensis (O. hupensis) is the only intermediate host of Schistosoma japonicum (S. japonicum), O. hupensis residing in different geographical regions display morphological differences and genetic variations, along with varying susceptibility to S. japonicum. In this study, we sequenced 26 complete mitochondrial genome of O. hupensis robertsoni Yunnan strain (O. h. r. Yunnan strain), the length of genome ranged from 15,181 to 15,187 bp, and the base composition of the genome was A+T (67.5%) and G+C content (32.5%). This genome encoded 37 genes, including 13 protein-coding genes, 2 rRNA genes, 22 tRNA genes and a non-coding region rich in A+T. Additional, we retrieved 14 other region O. hupensis of complete mitochondrial sequences from GenBank. The phylogenetic trees and homology analysis confirmed that O. hupensis robertsoni is subdivided into Yunnan strain and Sichuan strain, and O. h. r. Yunnan strain is subdivided into two subbranches, "Yunnan North" and "Yunnan South", the samples exhibited over 97% homology. This work reported the first mitochondrial genome of O. h. r. Yunnan strain, which could be used as an important reference genome for O. hupensis, and also provide a molecular biology-based theoretical foundation for understanding the genetic differentiation of O. hupensis.

genomics↗

bioRxiv2023

Integrative analysis reveals therapeutic potential of pyrvinium pamoate in Merkel cell carcinoma

Merkel Cell Carcinoma (MCC) is an aggressive neuroendocrine cutaneous malignancy arising from either ultraviolet-induced mutagenesis or Merkel cell polyomavirus (MCPyV) integration. Despite extensive research, our understanding of the molecular mechanisms driving the transition from normal cells to MCC remains limited. To address this knowledge gap, we assessed the impact of inducible MCPyV T antigens on normal human fibroblasts by performing RNA sequencing. Our data uncovered changes in expression and regulation of Wnt signaling pathway members. Building on this observation, we bioinformatically evaluated various Wnt pathway perturbagens for their ability to reverse the MCC gene expression signature and identified pyrvinium pamoate, an FDA-approved anthelminthic drug known for its anti-tumor activity in other cancers. Leveraging transcriptomic, network, and molecular analyses, we found that pyrvinium targets multiple MCC vulnerabilities. Pyrvinium not only reverses the neuroendocrine features of MCC by modulating canonical and non-canonical Wnt signaling but also inhibits cancer cell growth by activating p53-mediated apoptosis, disrupting mitochondrial function, and inducing endoplasmic reticulum stress. Finally, we demonstrated that pyrvinium reduces tumor growth in an MCC mouse xenograft model. These findings offer a new understanding of the role of Wnt signaling in MCC and highlight the utility of pyrvinium as a potential treatment for MCC.

cancer biology↗

bioRxiv2023

Resting state global brain activity induces bias in fMRI motion estimates

Head motion is a significant source of artifacts in resting-state fMRI (rsfMRI) studies and has been shown to affect resting-state functional connectivity (rsFC) measurements. In many rsfMRI studies, motion parameters estimated from volume registration are used to characterize head motion and to mitigate motion artifacts in rsfMRI data. While prior task-based fMRI studies have shown that task-evoked brain activations may induce temporally correlated bias in the motion estimates, resulting in artificial activations after registration, relatively little is known about neural-related bias in rsfMRI motion parameters. In this study, we demonstrate that neural-related bias exists in rsfMRI motion estimates and characterize the potential effects of the bias on rsFC estimates. Using a public multi-echo rsfMRI dataset, we use the differences between motion estimates from the first echo and second echo data as a measure of neural-induced bias. We show that the resting-state global activity of the brain, as characterized with the global signal (GS), induces bias in the motion estimates in the y- and z-translational axes. Furthermore, we demonstrate that the GS-related bias reflects superior-inferior and anterior-posterior asymmetries in the GS beta coefficient map. Finally, we demonstrate that regression with biased motion estimates can negatively bias rsFC estimates and also reduce rsFC differences between young and old subjects.

neuroscience↗

bioRxiv2023

Oncogenic RAS-Pathway Activation Drives Oncofetal Reprogramming and Creates Therapeutic Vulnerabilities in Juvenile Myelomonocytic Leukemia

Aberrant fetal gene expression facilitates tumor-specific cellular plasticity by hijacking molecular programs of embryogenesis1. Persistent fetal gene signatures in childhood malignancies are typically explained by their prenatal origins2-6. In contrast, reactivation of fetal gene expression is considered a consequence of oncofetal reprogramming (OFR) in adult malignancies and is associated with aggressive disease7-10. To date, OFR has not been described in the context of childhood malignancies. Here, we performed a comprehensive multi-layered molecular characterization of juvenile myelomonocytic leukemia (JMML) and identified OFR as a hallmark of aggressive JMML. We observed that hematopoietic stem cells (HSCs) aberrantly express mixed developmental programs in JMML. Expression of fetal gene signatures combined with a postnatal epigenetic landscape suggested OFR, which was validated in a JMML mouse model, demonstrating that postnatal activation of RAS signaling is sufficient to induce fetal gene signatures. Integrative analysis identified the fetal HSC maturation marker CD52 as a novel therapeutic target for aggressive JMML. Anti-CD52 treatment depleted human JMML HSCs and disrupted disease propagation in vivo. In summary, this study implicates OFR, defined as postnatal acquisition of fetal transcription signatures, in the pathobiology of a childhood malignancy. We provide evidence for the direct involvement of oncogenic RAS signaling in OFR. Finally, we demonstrate how OFR can be leveraged for the development of novel treatment strategies. Highlights{blacksquare} Epigenomic and transcriptomic landscape of juvenile myelomonocytic leukemia (JMML) in the context of hematopoietic development. {blacksquare}The presence of fetal transcription signatures in childhood malignancies is not indicative of a developmental maturation block. {blacksquare}High-risk JMML is characterized by oncofetal reprogramming of postnatal hematopoietic stem cells (HSCs). {blacksquare}RAS-pathway mutations induce fetal-like gene expression signatures in murine postnatal HSCs. {blacksquare}The fetal maturation marker CD52 is a novel therapeutic target in high-risk JMML.

cancer biology↗

bioRxiv2023

Molecular epidemiology of Cercospora leaf spot on resistant and susceptible sugar beet hybrids

Cercospora leaf spot (CLS), caused by Cercospora beticola, is a major foliar disease impacting sugar beet production worldwide. The development of new resistant sugar beet hybrids is a powerful tool to better manage the disease, but it is unclear how these hybrids affect CLS epidemiology. We used a molecular epidemiology approach to study natural epidemics of CLS affecting two susceptible and two resistant sugar beet hybrids at two field sites. Infected plants were geotagged on a weekly basis. Isolations of C. beticola were made from infected leaves and genotyped using six simple sequence repeat loci to identify clones. We determined that CLS epidemics had a later onset in plots planted to resistant hybrids, but once the pathogen established an infection, there was little difference between resistant and susceptible hybrids in the probability of localized spread and dispersal. We found that different clones often infected the same leaf and that clusters of infected plants were often colonized by a mixture of clones. There was little overall difference in genetic diversity between resistant and susceptible hybrids, however genotypic evenness differed at one site. In this site we found one genotype restricted to the resistant cultivars at a high frequency. At the end of the epidemic infections were not randomly distributed across the fields and we found that a single clone could spread over a distance of 100 m during a growing season.

pathology↗

bioRxiv2023

APOE4 poses opposite effects of plasma LDL on white matter integrity in older adults

INTRODUCTIONAPOE4 is a strong genetic risk factor of Alzheimers disease and is associated with changes in metabolism. However, the interactive relationship between APOE4 and plasma metabolites on the brain remains largely unknown. MEHODSIn the UK Biobank, we investigated the moderation effects of APOE4 on the relationship between 249 plasma metabolites derived from nuclear magnetic resonance spectroscopy on whole-brain white matter integrity, measured by fractional anisotropy using diffusion magnetic resonance imaging. RESULTSThe increase in the concentration of metabolites, mainly LDL and VLDL, is associated with a decrease in white matter integrity (b= -0.12, CI= [-0.14, -0.10]) among older APOE4 carriers, whereas an increase (b= 0.05, CI= [0.04, 0.07]) among non-carriers, implying a significant moderation effect of APOE4 (b= -0.18, CI= [-0.20,-0.15]). DISCUSSIONThe results suggest that lipid metabolism functions differently in APOE4 carriers compared to non-carriers, which may inform the development of targeted interventions for APOE4 carriers to mitigate cognitive decline.

neuroscience↗

bioRxiv2023

Regulation of NRF2 by Phosphoinositides and Small Heat Shock Proteins

Reactive oxygen species (ROS) are generated by aerobic metabolism, and their deleterious effects are buffered by the cellular antioxidant response, which prevents oxidative stress. The nuclear factor erythroid 2-related factor 2 (NRF2) is a master transcriptional regulator of the antioxidant response. Basal levels of NRF2 are kept low by ubiquitin-dependent degradation of NRF2 by E3 ligases, including the Kelch-like ECH-associated protein 1 (KEAP1). Here, we show that the stability and function of NRF2 is regulated by the type I phosphatidylinositol phosphate kinase {gamma} (PIPKI{gamma}), which binds NRF2 and transfers its product phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2) to NRF2. PtdIns(4,5)P2 binding recruits the small heat shock protein HSP27 to the complex. Silencing PIPKI{gamma} or HSP27 destabilizes NRF2, reduces expression of its target gene HO-1, and sensitizes cells to oxidative stress. These data demonstrate an unexpected role of phosphoinositides and HSP27 in regulating NRF2 and point to PIPKI{gamma} and HSP27 as drug targets to destabilize NRF2 in cancer. In briefPhosphoinositides are coupled to NRF2 by PIPKI{gamma}, and HSP27 is recruited and stabilizes NRF2, promoting stress-resistance.

cancer biology↗

bioRxiv2023

A stagewise response to mitochondrial dysfunction in mitochondrial DNA maintenance disorders

Mitochondrial DNA deletions clonally expand in skeletal muscle of patients with mtDNA maintenance disorders, impairing mitochondrial oxidative phosphorylation dysfunction. Previously we have shown that these mtDNA deletions originally arise and accumulate in the perinuclear mitochondria causing localised mitochondrial dysfunction before spreading through the muscle fibre. We believe that mito-nuclear signalling is a key contributor in this process. To further understand the role of mito-nuclear signalling, we use imaging mass cytometry to characterise the levels of mitochondrial respiratory complexes I-IV and ATP synthase alongside a mitochondrial mass marker, in a cohort of patients with mtDNA maintenance dosirders. We then expanded this panel to include protein markers of key signalling pathways to investigate the cellular response in fibres with different combinations of oxidative phosphorylation dysfunction and in ragged red fibres. We find CI and CIV deficiency to be most common, with a smaller proportion of cells that are also CIII and/or CV deficient. Interestingly, we also note that in cells deficient for one or more complexes, any complexes which are not deficient are commonly upregulated beyond the increase of mitochondrial mass typically observed in ragged red fibres. We further find that oxidative phosphorylation deficient fibres exhibit an increase in abundance of proteins involved in the proteostasis e.g. HSP60 and LONP1, and mitochondrial protein synthesis e.g. PHB1. Our analysis suggests that the cellular response to mitochondrial dysfunction changes depending on the combination of deficient oxidative phosphorylation complexes in each cell.

cell biology↗

bioRxiv2023

Theranostic multifunctional lipid nanoparticles containing curcumin for integrated imaging and stabilizing vulnerable atherosclerotic plaques through an "eat-me" signal

BACKGROUNDCurcumin has emerged as a promising candidate capable of polarization of macrophages, which promote the stability of atherosclerotic plaque. Nevertheless, a notable limitation lies in the non-specific nature of curcumins targeting. The present study endeavors to harness multifunctional lipid nanoparticles (MLNPs), which could both facilitate imaging and achieve targeted delivery of curcumin specifically to inflammatory macrophages, to effectively counteract vulnerable plaque and mitigate the risk of ischemic events. METHODSThe term "MLNPs", for targeted delivery of curcumin using multimodal imaging techniques including single photon emission computed tomography (SPECT) and magnetic resonance imaging (MRI), refers to a new type of nanoparticle designed to specifically target and modulate macrophages with phagocytic function. These nanoparticles are cholesteryl-9-carboxynonanoate-(125I-iron oxide nanoparticle/Cur)-lipid-coated nanoparticles [9-CCN-(125I-ION/Cur)-LNPs], which carry hybrid imaging agents. These agents are combinations of 125I-ION and lipids that contain phagocytic "eat-me" signals, which induces macrophages to swallow MLNPs. RESULTSThe accumulation of the devised 9-CCN-(125I-ION/Cur)-LNPs on the unstable plaque of animal models in vivo was accurately reflected and lesions were highlighted by both SPECT and MRI. The intense radioactive signals on SPECT images facilitated the identification and quantification of the target lesion, while MRI based on ION particles facilitated the visualization of the focal localization and volumetry of atherosclerotic plaque. The targeted distribution of the unstable plaque in the rabbit aorta was further confirmed by ex vivo planar images of nuclide and Prussian blue staining for ION. Additionally, 9-CCN-(125I-ION/Cur)-LNPs were found to specifically and effectively bind to the pro-inflammatory M1 macrophages present in the unstable plaque, resulting in the accumulation of radionuclide and hypointensity on T2W images. CONCLUSIONSThe 9-CCN-(125I-ION/Cur)-LNPs demonstrated remarkable capability in the delivery of both 125I-ION and curcumin to macrophages, ultimately resulting in M1-M2 macrophage polarization, which may offer valuable insights into addressing unstable atherosclerotic plaque.

neuroscience↗

bioRxiv2023

V-pipe 3.0: a sustainable pipeline for within-sample viral genetic diversity estimation

The large amount and diversity of viral genomic datasets generated by next-generation sequencing technologies poses a set of challenges for computational data analysis workflows, including rigorous quality control, adaptation to higher sample coverage, and tailored steps for specific applications. Here, we present V-pipe 3.0, a computational pipeline designed for analyzing next-generation sequencing data of short viral genomes. It is developed to enable reproducible, scalable, adaptable, and transparent inference of genetic diversity of viral samples. By presenting two large-scale data analysis projects, we demonstrate the effectiveness of V-pipe 3.0 in supporting sustainable viral genomic data science.

bioinformatics↗

bioRxiv2023

Acute avoidance of hydrogen sulfide is modulated by external and internal states in C. elegans

Hydrogen sulfide (H2S) acts as an energy source, a toxin, and a gasotransmitter across diverse biological contexts. We use the robust locomotory responses of Caenorhabditis elegans to high levels of H2S to elucidate the molecular mechanisms underlying its acute and adaptive responses. We find that the H2S-evoked behavioral response is shaped by multiple environmental factors including oxygen (O2) levels and nutritional state, and is modulated by various pathways such as insulin, TGF-{beta}, and HIF-1 signaling, as well as by input from O2-sensing neurons. Prolonged exposure to H2S activates HIF-1 signaling, leading to the upregulation of stress-responsive genes, including those involved in H2S detoxification. This promotes an adaptive state in which locomotory speed is reduced in H2S, while responsiveness to other stimuli is preserved. In mutants deficient in HIF-1 signaling, iron storage, and detoxification mechanisms, animals display a robust initial response but rapidly enter a sleep-like behavior characterized by reduced mobility and diminished responsiveness to subsequent sensory stimuli. Furthermore, while acute production of mitochondria-derived reactive O2 species (ROS) appears to initiate the avoidance response to H2S, persistently high ROS promotes an adaptive state, likely by activating various stress-response pathways, without substantially compromising cellular H2S detoxification capacity. Taken together, our study provides comprehensive molecular insights into the mechanisms through which C. elegans modulates and adapts its response to H2S exposure.

animal behavior and cognition↗

bioRxiv2023

The benzoxazinoid breakdown product 5-Methoxy-2-Nitrophenol has a dual function in maize defense against herbivory

Catabolism of plant secondary metabolites can yield bioactive breakdown products. However, these compounds often remain poorly characterized. Here, we report on the discovery, biosynthesis, and biological relevance of 5-Methoxy-2-Nitrophenol (5M2NP), a secondary metabolite breakdown product which accumulates in damaged maize tissues. We used mutant plants, biochemical complementation, and metabolomic analyses to determine the biosynthetic origin of 5M2NP. Additionally, we assessed 5M2NPs role in plant defense against herbivores. For this, we surveyed defense-associated responses (gene expression, phytohormones, volatile organic compounds) in wounded, 5M2NP-supplemented maize leaves, and performed bioassays with herbivorous insects. We found that 5M2NP accumulation upon tissue disruption is contingent upon a functional benzoxazinoid biosynthesis pathway. Labeling experiments demonstrated that 5M2NP is derived from DIMBOA. Physiological doses of exogenous 5M2NP increased the wound-induced expression of defense genes and emission of terpenoids. Additionally, 5M2NP exhibited antibiotic and antixenotic activities towards both generalist and specialist herbivores in nano-to micromolar quantities. We conclude that 5M2NP, which represents a novel class of plant-derived compounds, can act as a direct defense and a defense modulator. 5M2NP thus expands the functional repertoire of benzoxazinoids and likely contributes to their protective function against insect herbivores. The discovery of 5M2NP highlights the multifunctionality of plant secondary metabolites and their breakdown products.

plant biology↗

bioRxiv2023

Recurrent hybridization and gene flow shaped Norway and Siberian spruce evolutionary history over multiple glacial cycles

Over the last decades, extensive genome-wide resequencing studies have highlighted the extent of hybridization and introgression between closely related species. Animal and plant species went through cycles of contractions and expansions as a result of glacial cycles. These repeated sequences of reproductive isolation and admixture at continental scales have led to the accumulation over time of an ancient, deep-seated and complex genetic structure. This structure was blurred by extensive gene flow, or reinforced by strong local adaptation. This already multi-layered structure has often been further enhanced by hybridization. We investigated this complexity in Norway spruce (Picea abies) and Siberian spruce (P. obovata), two closely related species dominating Eurasian boreal forests and forming a vast hybrid zone. Here, we genotyped 542 individuals of both species and their hybrids at 480K SNPs. Individuals came from 55 populations, extending from western Europe to Siberia with a focus on the main hybrid zone. Despite extensive gene flow and a clear Isolation-by-Distance pattern at the continental scale, distinct genetic clusters emerged, indicating barriers and corridors to migration. Coalescent-based demographic inferences revealed that Norway and Siberian spruce repeatedly hybridized during the Pleistocene with introgression pattern varying depending on the latitude. In northern ranges, P. obovata expanded into P. abies while P. abies expanded into P. obovata in the southern parts. Two cryptic refugia located in the large hybrid zone played a critical role in shaping the current distribution of the two species. Our study highlights the importance of considering the whole species complex instead of separate entities to shed light on their complex demographic histories.

evolutionary biology↗

bioRxiv2023

CircSMAD3 represses VSMC phenotype switching and neointima formation via promoting hnRNPA1 ubiquitination degradation

AimsCircular RNAs (circRNAs) are novel regulatory RNAs with high evolutionary conservation and stability, making them attractive therapeutic agents for various vascular diseases. SMAD family is a downstream mediator of the canonical TGF{beta} signalling pathway and has been considered a critical regulator in vascular injury. However, the role of circRNAs derived from the SMAD family members in vascular physiology remains unclear. Therefore, this study aimed to identify a functional circRNA derived from the SMAD family and elucidate its potential as an effective therapeutic agent for vascular proliferative diseases. Methods and ResultsWe initially identified potential functional circRNAs originating from the SMAD family using integrated transcriptome screening. circSMAD3, derived from the SMAD3 gene, was identified to be significantly downregulated in vascular injury and atherosclerosis. Transcriptome analysis was conducted to comprehensively illustrate the pathways modulated by circRNAs. Functionally, circSMAD3 repressed VSMC proliferation and phenotype switching in vitro evidenced by morphological assays and ameliorated arterial injury-induced neointima formation in vivo. Mechanistically, circSMAD3 interacted with heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1) within the nucleus, enhanced its interaction with E3 ligase WD repeat domain 76 (WDR76) to promote hnRNPA1 ubiquitination degradation, facilitated p53 pre-RNA splicing, activated p53{gamma} signalling pathway, and finally suppressed VSMC proliferation and phenotype switching. ConclusionOur study identifies circSMAD3 as a novel epigenetic regulator that suppresses VSMC proliferation and phenotype switching, thereby attenuating vascular remodelling and providing a new circRNA-based therapeutic strategy for cardiovascular diseases.

molecular biology↗