Biology subjects

Gao, L.

Publications and source records attributed to Gao, L..

At least 109 records · Page 6Linked to original sources

bioRxiv2023

Inhibition of HSP90 distinctively modulates the global phosphoproteome of Leishmania mexicana developmental stages

Heat shock protein 90 (HSP90) is an evolutionary conserved chaperone protein that plays a central role in the folding and maturation of a large array of client proteins. In the unicellular parasite Leishmania, the etiological agent of the neglected tropical disease leishmaniasis, treatment of the classical HSP90 inhibitor tanespimycin leads to dose- and time-dependent differentiation from promastigote to amastigote stage, eventually culminating in parasite killing. Although this suggests a crucial role of the HSP90 in the life cycle control of Leishmania, the underlying molecular mechanism remains unknown. Using a combination of phosphoproteome enrichment and tandem mass tag (TMT) labelling-based quantitative proteomic mass spectrometry (MS), we robustly identified and quantified 1,833 phosphorylated proteins across three life cycle stages of Leishmania mexicana (L. mexicana) parasite. Protein kinase domain was the most enriched protein domain in the L. mexicana phosphoproteome. Additionally, this study systematically characterised the perturbing effect of HSP90 inhibition on the global phosphoproteome of L. mexicana across its life cycle stages and showed that the tanespimycin treatment causes substantially distinct molecular effects in promastigote and amastigote forms. Whilst phosphorylation of HSP90 and its co-chaperon HSP70 was decreased in amastigotes, the opposite effect was observed in promastigotes. Additionally, our results showed that while kinase activity and microtubule motor activity are highly represented in the negatively affected phosphoproteins of the promastigotes, whereas ribosomal proteins, protein folding, and proton channel activity are preferentially enriched in the perturbed amastigote phosphoproteome. Our results also show that RNA helicase domain was distinctively enriched among the positively affected RNA-binding amastigote phosphoproteome. This study reveals the dramatically different ways the HSP90 inhibition stress modulates the phosphoproteome of the pathogenic amastigotes and provides in-depth insight into the scope of selective molecular targeting in the therapeutically relevant amastigote forms. IMPORTANCEIn the unicellular parasites Leishmania spp., the etiological agents of leishmaniasis, a complex infectious disease that affects 98 countries in 5 continents, chemical inhibition of HSP90 protein, a master regulator of protein homeostasis, leads to differentiation from promastigote to amastigote stage, eventually culminating in parasite death. However, the underlying molecular mechanism remains unknown. Recent studies suggest a fundamentally important role of RNA-binding proteins (RBPs) in regulating the downstream effects of the HSP90 inhibition in Leishmania. Phosphorylation-dephosphorylation dynamics of RNA-binding proteins (RBPs) in higher eukaryotes serves as an important on/off switch to regulate RNA processing and decay in response to extracellular signals and cell cycle check points. In the current study, using a combination of highly sensitive tandem mass tag (TMT) labelling-based quantitative proteomic mass spectrometry (MS) and robust phosphoproteome enrichment, we show for the first time that the HSP90 inhibition distinctively modulates global protein phosphorylation landscapes in the different life cycle stages of Leishmania, shedding light into a crucial role of the posttranslational modification in the differentiation of the parasite under HSP90 inhibition stress. This work provides insights into the importance of HSP90-mediated protein cross-talks and regulation of phosphorylation in Leishmania, thus significantly expanding our knowledge of the posttranslational modification in Leishmania biology.

microbiology↗

bioRxiv2023

Whole-genome Omics delineates the function of CCM1 within the CmPn networks

IntroductionCerebral cavernous malformations (CCMs) are abnormal dilations of brain capillaries that increase the risk of hemorrhagic strokes. Mutations in the KRIT1, MGC4607, and PDCD10 genes cause CCMs, with mutations in CCM1 accounting for about 50% of familial cases. The disorder exhibits incomplete penetrance, meaning that individuals with CCM may appear normal initially, but once symptoms manifest, their brains have already suffered irreversible damage. Compromised blood-brain barrier (BBB) is crucial in regulating the flow of substances between the blood and the central nervous system, which can result in hemorrhagic CCMs. Progesterone and its derivatives have been studied for their impact on maintaining BBB integrity. CCM2 interacts with CCM1 and CCM3, forming the CCM signaling complex (CSC), which connects classic and non-classic progesterone signaling to establish the CmPn signaling network, vital in preserving BBB integrity. MethodsThe study aimed to explore the relationship between CCM1 and key pathways of the CmPn signaling network, utilizing a toolset comprising three mouse embryonic fibroblast lines (MEFs) with distinct CCM1 expression levels. Omics and systems biology analysis were performed to investigate Ccm1-mediated signaling within the CmPn signaling network. ResultsThe findings suggest that CCM1 plays a critical role in controlling cellular processes in response to different progesterone-mediated actions within CmPn/CmP signaling networks, partly by regulating gene transcription. This function is crucial for preserving the integrity of microvessels, indicating that targeting CCM1 could hold promise as a therapeutic approach for this condition.

molecular biology↗

bioRxiv2023

Building a genetic and epigenetic predictive model of breast cancer intrinsic subtypes using large-scale data and hierarchical structure learning

Breast cancer subtyping is a difficult clinical and scientific challenge. The prevalent Prediction Analysis of Microarray of 50 genes (PAM50) system and its Immunohistochemistry (IHC) surrogate showed significant inconsistencies. This is because of the limited training samples, highly variable molecular features and in-efficient strategies used in these classifiers. The rapid development of early screening technologies, especially in the field of circulating tumor DNA, has also challenged the subtyping of breast cancer at the DNA level. By integrating large-scale DNA-level data and using a hierarchical structure learning algorithm, we developed Unified Genetic and Epigenetic Subtyping (UGES), a new intrinsic subtype classifier. The benchmarks showed that the use of all classes of DNA alterations worked much better than single classes, and that the multi-step hierarchical learning is crucial, which improves the overall AUC score by 0.074 compared to the one-step multi-classification method. Based on these insights, the ultimate UGES was trained as a three-step classifier on 50831 DNA features of 2065 samples, including mutations, copy number aberrations, and methylations. UGES achieved overall AUC score 0.963, and greatly improved the clinical stratification of patients, as each stratas survival difference became statistically more significant p-value=9.7e-55 (UGES) vs 2.2e-47 (PAM50). Finally, UGES identified 52 subtype-level DNA biomarkers that can be targeted in early screening technology to significantly expand the time window for precision care. The analysis code is freely available at https://github.com/labxscut/UGES.

bioinformatics↗

bioRxiv2023

A Citrullus genus super-pangenome reveals extensive variations in wild and cultivated watermelons and sheds light on watermelon evolution and domestication

Sweet watermelon (Citrullus lanatus subsp. vulgaris) is among the most important vegetable crops in the world. Wild relatives are important resources for watermelon breeding. Here we report high-quality reference genomes of three wild watermelons, C. mucosospermus, C. amarus and C. colocynthis, and the divergence and genome evolution of different Citrullus species. Using genomic data from 547 watermelon accessions spanning four Citrullus species, we construct a super-pangenome to represent the Citrullus gene repertoire and provide a catalogue of orthologous relationships among species. Gene presence/absence variation analysis uncovers many disease resistance genes that are missing in cultivated watermelons, as well as genes with significantly different occurrence frequencies between populations that might underlie watermelon evolution and domestication. We revisit watermelon domestication using the recently identified wild progenitor, Kordofan melon, which provides insights into the domestication of fruit bitterness, sweetness and flesh coloration. The Citrullus super-pangenome provides a valuable resource for breeding and biological discovery, and our comparative genomic analyses shed additional light on watermelon evolution and domestication.

plant biology↗

bioRxiv2023

Transcriptional profiling of mucus production and modification in rhesus macaque endocervical cells under hormonal regulation

ObjectiveEndocervical mucus production is a key regulator of fertility throughout the menstrual cycle. With cycle-dependent variability in mucus quality and quantity, cervical mucus can either facilitate or block sperm ascension into the upper female reproductive tract. This study seeks to identify genes involved in the hormonal regulation of mucus production, modification, and regulation through profiling the transcriptome of endocervical cells from the non-human primate, the Rhesus Macaque (Macaca mulatta). DesignExperimental. SettingTranslational science laboratory. InterventionWe treated differentiated primary endocervical cultures with estradiol (E2) and progesterone (P4) to mimic peri-ovulatory and luteal-phase hormonal changes. Using RNA-sequencing, we identified differential expression of gene pathways and mucus producing and modifying genes in cells treated with E2 compared to hormone-free conditions and E2 compared to E2-primed cells treated with P4. Main Outcome MeasuresWe pursued differential gene expression analysis on RNA-sequenced cells. Sequence validation was done using qPCR. ResultsOur study identified 158 genes that show significant differential expression in E2-only conditions compared to hormone-free control, and 250 genes that show significant differential expression in P4-treated conditions compared to E2-only conditions. From this list, we found hormone-induced changes in transcriptional profiles for genes across several classes of mucus production, including ion channels and enzymes involved in post-translational mucin modification that have not previously been described as hormonally regulated. ConclusionOur study is the first to use an in vitro culture system to create an epithelial-cell specific transcriptome of the endocervix. As a result, our study identifies new genes and pathways that are altered by sex-steroids in cervical mucus production.

molecular biology↗

bioRxiv2023

Arabidopsis NF-YCs interact with CRY2 and PIF4/5 to repress blue light-mediated hypocotyl growth

Plants can not move automatically, thus they have to perceive the changing environment (light, temperate and so on) by developing the adapted phenotypes. Light-induced hypocotyl length is an ideal phenotype for studying how plants response to light. So far, many signaling components in light-induced hypocotyl growth have been reported. Here, we focused on identifying transcription factors (TFs) involved in blue light-induced hypocotyl growth by constructing Arabidopsis TFs overexpressing lines and screening blue light-induced hypocotyl length. Finally, we found that three NF-YC proteins, NF-YC7, NF-YC5 and NF-YC8 (NF-YCs as short name), develop longer hypocotyls than the wild type under blue light. While deficient mutants, nf-yc5nf-yc7 and nf-yc7nf-yc8, fail to promote the hypocotyl elongation under blue light. NF-YCs physically interacted with CRY2 and PIF4/5, while the NF-YCs-PIF4/5 interactions were repressed by CRY2. Moreover, overexpression of CRY2 or deficiency of PIF4/5 repressed the hypocotyl elongation induced by NF-YC7 under blue light. Further investigation revealed that NF-YC7 increased the blue light-induced CRY2 degradation and regulated the activities of PIF4/5. Taking together, this study provided a new insight into that NF-YCs function as CRY2-and PIF4/5-interacting proteins and modulate their stabilization to repress the blue light-mediated hypocotyl growth. Author SummaryLight is an essential environmental factor for plants growth and development. Plants response to light signaling by displaying short hypocotyls, green leaves, and so on. The mechanisms of light responding to light have aroused extensive attention. In this study, we clarified that NF-YC family members NF-YC5/7/8 interact with CRY2, PIF4/5 and modulate their stabilization to repress the blue light-mediated hypocotyl growth. It was the first time for reporting NF-Y family members function as CRY2-and PIF4/5-interacting proteins. Therefore, this study provides a novel understanding how plants adapt to light.

genetics↗

bioRxiv2023

Targeted repression of DNA topoisomerase I by CRISPRi reveals a critical function for it in the Chlamydia trachomatis developmental cycle

Chlamydia trachomatis is an obligate intracellular bacterium that is responsible for the most prevalent bacterial sexually transmitted infections. Changes in DNA topology in this pathogen have been linked to its pathogenicity-associated developmental cycle. Here, evidence is provided that the balanced activity of DNA topoisomerases (Topos) contributes to Chlamydia developmental processes. Utilizing catalytically inactivated Cas12 (dCas12) based-clustered regularly interspaced short palindromic repeats interference (CRISPRi) technology, we demonstrate targeted knockdown of chromosomal topA transcription in C. trachomatis without detected toxicity of dCas12. Repression of topA impaired the growth of C. trachomatis mostly through disruption of its differentiation from a replicative form to an infectious form. Consistent with this, expression of late developmental genes of C. trachomatis was downregulated while early genes maintained their expression. Importantly, the growth defect associated with topA knockdown was rescued by overexpressing topA at an appropriate degree and time, directly linking the growth patterns to the levels of topA expression. Interestingly, topA knockdown had pleiotropic effects on DNA gyrase expression, indicating a potential compensatory mechanism for survival to offset TopA deficiency. C. trachomatis with topA knocked down displayed hypersensitivity to moxifloxacin that targets DNA gyrase in comparison with the wild type. These data underscore the requirement of integrated topoisomerase actions to support the essential development and transcriptional processes of C. trachomatis. ImportanceWe used genetic and chemical tools to demonstrate the relationship of topoisomerase activities and their obligatory role for the chlamydial developmental cycle. Successfully targeting the essential gene topA with a CRISPRi approach, using dCas12, in C. trachomatis indicates that this method will facilitate the characterization of the essential genome. These findings have an important impact on our understanding of the mechanism(s) by which well-balanced topoisomerase activities enable C. trachomatis to adapt to unfavorable growth conditions imposed by antibiotics.

microbiology↗

bioRxiv2022

Learning predictive models of tissue cellular neighborhoods from cell phenotypes with graph pooling

It remains poorly understood how different cell types organize and coordinate with each other to support tissue functions. We describe CytoCommunity for identification of tissue cellular neighborhoods (TCNs) based on cell phenotypes and their spatial distributions. CytoCommunity learns a mapping directly from cell phenotype space to TCN space by a graph neural network model without using additional gene or protein expression features and is thus applicable to tissue imaging data with a small number of measured features. By leveraging graph pooling, CytoCommunity enables de novo identification of condition-specific TCNs under the supervision of image labels. Using various types of single-cell-resolution spatial proteomics and transcriptomics images, we demonstrate that CytoCommunity can identify TCNs of variable sizes with substantial improvement over existing methods. To further evaluate the ability of CytoCommunity for discovering condition-specific TCNs by supervised learning, we apply it to colorectal and breast cancer tissue images with clinical outcome information. Our analysis reveals novel granulocyte- and cancer associated fibroblast-enriched TCNs specific to high-risk tumors as well as altered tumor-immune and tumor-stromal interactions within and between TCNs compared to low-risk tumors. CytoCommunity represents the first computational tool for end-to-end unsupervised and supervised analyses of single-cell spatial maps and enables direct discovery of conditional-specific cell-cell communication patterns across variable spatial scales.

bioinformatics↗

bioRxiv2022

Altered GC- and AT-biased genotypes of Ophiocordyceps sinensis in the stromal fertile portions and ascospores of natural Cordyceps sinensis

ObjectiveTo examine multiple genotypes of Ophiocordyceps sinensis in a semi-quantitative manner in the stromal fertile portion (SFP) densely covered with numerous ascocarps and ascospores of natural Cordyceps sinensis and to outline the dynamic alterations of the coexisting O. sinensis genotypes in different developmental phases. MethodsMature Cordyceps sinensis specimens were harvested and continuously cultivated in our laboratory (altitude 2,254 m). The SFPs (with ascocarps) and fully and semi-ejected ascospores were collected for histological and molecular examinations. Biochip-based single nucleotide polymorphism (SNP) MALDI-TOF mass spectrometry (MS) was used to genotype multiple O. sinensis mutants in the SFPs and ascospores. ResultsMicroscopic analysis revealed distinct morphologies of the SFPs (with ascocarps) before and after ascospore ejection and SFP of developmental failure, which, along with the fully and semi-ejected ascospores, were subjected to SNP MS genotyping analysis. Mass spectra showed the coexistence of GC- and AT-biased genotypes of O. sinensis that were genetically and phylogenetically distinct in the SFPs before and after ejection and of developmental failure and in fully and semi-ejected ascospores. The intensity ratios of MS peaks were dynamically altered in the SFPs and the fully and semi-ejected ascospores. Mass spectra also showed transversion mutation alleles of unknown upstream and downstream sequences with altered intensities in the SFPs and ascospores. Genotype #5 of AT-biased Cluster-A maintained a high intensity in all SFPs and ascospores. An MS peak with a high intensity containing AT-biased Genotypes #6 and #15 in pre-ejection SFPs was significantly attenuated after ascospore ejection. The abundance of Genotypes #5-6 and #16 of AT-biased Cluster-A was differentially altered in the fully and semi-ejected ascospores that were collected from the same Cordyceps sinensis specimens. ConclusionMultiple O. sinensis genotypes coexisted in different combinations with altered abundances in the SFPs prior to and after ejection, the SFP of developmental failure, and the two types of ascospores of Cordyceps sinensis, demonstrating their genomic independence. Metagenomic fungal members present in different combinations and with dynamic alterations play symbiotic roles in different compartments of natural Cordyceps sinensis.

molecular biology↗

bioRxiv2022

Tunable image-mapping optical coherence tomography

We present tunable image-mapping optical coherence tomography (TIM-OCT), which can provide optimized imaging performance for a given application by using a programmable phase-only spatial light modulator in a low-coherence full-field spectral-domain interferometer. The resultant system can provide either a high lateral resolution or a high axial resolution in a snapshot without moving parts. Alternatively, the system can achieve a high resolution along all dimensions through a multiple-shot acquisition. We evaluated TIM-OCT in imaging both standard targets and biological samples. Additionally, we demonstrated the integration of TIM-OCT with computational adaptive optics in correcting sample-induced optical aberrations.

bioengineering↗

bioRxiv2022

Decoding the Mouse Spinal Cord Locomotor Neural Network Using Tissue Clearing, Tissue Expansion and Tiling Light Sheet Microscopy Techniques

Decoding a biological neural network requires the structural information regarding the spatial organization, dendritic morphology, axonal projection and synaptic connection of the neurons in the network. Imaging physically sectioned nervous tissues using electron microscopy (EM) has been the only method to acquire such information. However, EM is inefficient for imaging and reconstructing large neural networks due to the low throughput and inability to target neural circuits of interest by labeling specific neuron populations genetically. Here, we present a method to image large nervous tissues from the cellular to synaptic level with high throughput using tiling light sheet microscopy combined with tissue clearing and tissue expansion techniques. We describe the method, demonstrate its capability and explore its utility for decoding large biological neural networks by studying the spinal cord locomotor neural network in genetically labeled fluorescent mice. We show our method could advance the decoding of large neural networks significantly.

neuroscience↗

bioRxiv2022

Underlying beneficial effects of Rhubarb on constipation-induced inflammation, disorder of gut microbiome and metabolism

BackgroundAlthough constipation is a common syndrome and a worldwide health problem. Constipation patients are becoming younger with a 29.6% overall prevalence in the children, which has captured great attention because of its epigenetic rejuvenation and recurrent episodes. Despite the usage of rhubarb to relieve constipation, novel targets and genes involved in target-relevant pathways with remarkable functionalities should still be sought after. Materials and methodsWe established a reliable constipation model in C57B/6N male mice using intragastric administration diphenoxylate and the eligible subjects received 600mg/25g rhubarb extraction to ameliorate constipation. Resultant constipation was morphological and genetically compared with the specimen from different groups. ResultsThe constipation mice exhibited thicker muscle layers, improved content of cytokines, including IL-17 and IL-23, and lower content of IL-22. The bacterial abundance and diversity varied tremendously. Notably, the alterations were reversed after rhubarb treatment. Additionally, SCFA and MLCFA were significantly influenced by constipation accompanied by enhanced expressions of SCFA receptors, GPR41 and GPR43. ConclusionThis thesis has provided an insight that rhubarb promoted the flexibility of collagen fiber, reduced pro-inflammatory cytokines and enhanced anti-inflammatory cytokines, and maintained intestinal microflora balance with potential effects on affecting the metabolism of fatty acids and polyamines.

pharmacology and toxicology↗

bioRxiv2022

Differential coexistence of multiple genotypes of Ophiocordyceps sinensis in the stromata, ascocarps and ascospores of natural Cordyceps sinensis

ObjectiveTo examine the differential occurrence of Ophiocordyceps sinensis genotypes in the stroma, stromal fertile portion (SFP) densely covered with numerous ascocarps, and ascospores of natural Cordyceps sinensis. MethodsImmature and mature C. sinensis specimens were harvested. Mature C. sinensis specimens were continuously cultivated in our laboratory (altitude 2,200 m). The SFPs (with ascocarps) and ascospores of C. sinensis were collected for microscopic and molecular analyses using species-/genotype-specific primers. Sequences of mutant genotypes of O. sinensis were aligned with that of Genotype #1 Hirsutella sinensis and compared phylogenetically using a Bayesian majority-rule method. ResultsFully and semiejected ascospores were collected from the same specimens. The semiejected ascospores tightly adhered to the surface of the asci as observed by the naked eye and under optical and confocal microscopies. The multicellular heterokaryotic ascospores showed uneven staining of nuclei. The immature and mature stromata, SFPs (with ascocarps) and ascospores were found to differentially contain several GC- and AT-biased genotypes of O. sinensis, Samsoniella hepiali, and an AB067719-type fungus. The genotypes within AT-biased Cluster-A in the Bayesian tree occurred in all compartments of C. sinensis, but those within AT-biased Cluster-B were present in immature and mature stromata and SPFs but absent in the ascospores. Genotype #13 of O. sinensis was present in semi-ejected ascospores and Genotype #14 in fully ejected ascospores. GC-biased Genotypes #13-14 featured large DNA segment substitutions and genetic material recombination between the genomes of the parental fungi (H. sinensis and the AB067719-type fungus). These ascosporic offspring genotypes combined with varying abundances of S. hepiali in the 2 types of ascospores participated in the control of the development, maturation and ejection of the ascospores. ConclusionMultiple genotypes of O. sinensis coexist differentially in the stromata, SFPs and 2 types of C. sinensis ascospores, along with S. hepiali and the AB067719-type fungus. The fungal components in different combinations and their dynamic alterations in the compartments of C. sinensis during maturation play symbiotic roles in the lifecycle of natural C. sinensis.

molecular biology↗

bioRxiv2022

Parallel analysis of RNA ends reveals global microRNA-mediated target RNA cleavage in maize

MicroRNAs (miRNAs) are endogenous 20-to 24-nucleotide (nt) noncoding RNAs that play important regulatory roles in many biological processes in eukaryotes. miRNAs modulate the expression of target genes at the post-transcriptional level by transcript cleavage or translational inhibition. Identification of miRNA target genes have been extensively investigated in Arabidopsis and rice, but an in-depth global analysis of miRNA-mediated target regulation is still lacking in maize. Here, we report a transcriptome-wide identification of miRNA targets by analyzing Parallel Analysis of RNA Ends (PARE) datasets derived from nine different tissues at five developmental stages of the maize (Zea mays L.) B73 cultivar. 246 targets corresponding to 60 miRNAs from 25 families were identified, including transcription factors and other genes. In addition, PARE analysis revealed that miRNAs guide specific target transcript cleavage in a tissue-preferential manner. Interestingly, primary transcripts of MIR159c and MIR169e were found to be cleaved by mature miR159 and miR169, respectively, indicating a positive-feedback regulatory mechanism in miRNA biogenesis. Moreover, several new miRNA-target gene pairs involved in seed germination were identified and experimentally validated. Our PARE analyses generated a wide and detailed miRNA-target interaction atlas, which provides a valuable resource for investigating the roles of miRNAs and their targets in maize.

plant biology↗

bioRxiv2022

Label-Free Hyperspectral Imaging and Deep-Learning Prediction of Retinal Amyloid β-Protein and Phosphorylated Tau

Alzheimers disease (AD) is a major risk for the aging population. The pathological hallmarks of AD--an abnormal deposition of amyloid {beta}-protein (A{beta}) and phosphorylated tau (pTau)--have been demonstrated in the retinas of AD patients, including in prodromal patients with mild cognitive impairment (MCI). A{beta} pathology, especially the accumulation of the amyloidogenic 42-residue long alloform (A{beta}42), is considered an early and specific sign of AD, and together with tauopathy, confirms AD diagnosis. To visualize retinal A{beta} and pTau, state-of-the-art methods use fluorescence. However, administering contrast agents complicates the imaging procedure. To address this problem, we developed a label-free hyperspectral imaging method to detect the spectral signatures of A{beta}42 and pS396-Tau and predicted their abundance in retinal cross sections. For the first time, we reported the spectral signature of pTau and demonstrated an accurate prediction of A{beta} and pTau distribution powered by deep learning. We expect our finding will lay the groundwork for label-free detection of AD at its very earliest roots. Significance StatementThe pathological hallmarks of Alzheimers disease (AD), amyloid {beta}-protein (A{beta}) and hyperphosphorylated (p)Tau protein have been characterized by a hyperspectral camera in terms of spectral signatures. The unique optical properties of the hallmark proteins on the broad visible light range enable label-free and high-resolution detection and virtual staining of abnormal deposition in the retina tissue, which will lay the groundwork for AD early diagnosis and AD development quantification.

bioengineering↗

bioRxiv2022

SARS-CoV-2 impacts the transcriptome and epigenome at the maternal-fetal interface in pregnancy

During pregnancy, the maternal-fetal interface plays vital roles in fetal development. Its disruption is frequently found in pregnancy complications. Recent works show increased incidences of adverse pregnancy outcomes in COVID-19 patients; however, the mechanism remains unclear. Here, we analyzed the molecular impacts of SARS-CoV-2 infection on the maternal-fetal interface. Generating bulk and single-nucleus transcriptomic and epigenomic profiles from COVID-19 patients and control samples, we discovered aberrant immune activation and angiogenesis patterns in patients. Surprisingly, retrotransposons were dysregulated in specific cell types. Notably, reduced enhancer activities of LTR8B elements were functionally linked to the downregulation of Pregnancy-Specific Glycoprotein genes in syncytiotrophoblasts. Our findings revealed that SARS-CoV-2 infection induced significant changes to the epigenome and transcriptome at the maternal-fetal interface, which may be associated with pregnancy complications. One-Sentence SummaryPregnant COVID-19 patients show placental epigenetic and transcriptional changes, associated with adverse pregnancy outcomes.

genomics↗

bioRxiv2022

Deciphering Hierarchical Chromatin Structures and Preference of Genomic Positions in Single Mouse Embryonic Stem Cells

The exploration of single-cell 3D genome maps reveals that chromatin domains are indeed physical structures presenting in single cells and domain boundaries vary from cell to cell. However, exhaustive analysis of regulatory factor binding or elements for preference of the formation of chromatin domains in single cells has not yet emerged. To this end, we first develop a hierarchical chromatin domain structure identification algorithm (named as HiCS) from individual single-cell Hi-C maps, with superior performance in both accuracy and efficiency. The results suggest that in addition to the known CTCF-cohesin complex, Polycomb, TrxG, pluripotent protein families and other multiple factors also contribute to shaping chromatin domain boundaries in single embryonic stem cells. Different cooperation patterns of regulatory factors decipher the preference of genomic position categories forming boundaries. And the most extensive six types of retrotransposons differentially distributed in these genomic position categories with preferential localization.

bioinformatics↗

bioRxiv2022

Induction of Anxiety-Like Phenotypes by Knockout of Cannabinoid Type-1 Receptor in Amygdala of Marmosets

The amygdala is an important hub for the regulation of emotions, which is crucial for elucidating cellular and molecular mechanisms of many mental diseases. In the central nervous system, the endocannabinoid system plays a key role in the regulation of emotions and mainly functions through the cannabinoid type-1 receptor (CB1R), which is encoded by the Cnr1 gene. Although CB1R is highly expressed in the amygdala of non-human primates, little is known about its function. Here, we investigated the function of CB1R by knocking out the CB1R in the amygdala of adult marmosets through regional delivery of AAV-SaCas9-gRNA. We found that CB1R knockout in the amygdala of marmosets induced anxiety-like behaviors, including disrupted night sleep, agitated psychomotor activity in new environments, and reduced social desire, but had no effect on hedonic state and fear response. Moreover, CB1R-knockout marmosets exhibited up-regulated plasma cortisol levels, suggesting increased stress. These results showed that knockout of CB1R in the amygdala induced anxiety-like phenotypes in marmosets and shed new light on the mechanisms underlying the regulation of anxiety by CB1R in the amygdala of non-human primates.

neuroscience↗