Biology subjects

Liu, Y.

Publications and source records attributed to Liu, Y..

At least 1,459 records · Page 81Linked to original sources

bioRxiv2023

The IRE1α/XBP1/Myomaker axis drives myoblast fusion in adult skeletal muscle

Skeletal muscle regeneration involves a signaling network that regulates the proliferation, differentiation, and fusion of muscle precursor cells to injured myofibers. Inositol requiring enzyme 1 alpha (IRE1) is one of the arms of the unfolded protein response (UPR) that regulates cellular proteostasis in response to ER stress. Here, we demonstrate that inducible deletion of IRE1 in adult muscle stem cells (i.e. satellite cells) of mice impairs skeletal muscle regeneration primarily through inhibiting myoblast fusion step. Knockdown of IRE1 or its downstream target, X-box protein 1 (XBP1), also inhibits fusion of cultured myoblasts during myogenesis. Genome-wide transcriptome analysis revealed that knockdown of IRE1 or XBP1 deregulates the gene expression of molecules involved in the regulation of myoblast fusion. The IRE1-XBP1 axis mediates the gene expression of multiple profusion molecules, including Myomaker (Mymk) during myogenic differentiation. Our study demonstrates that spliced XBP1 (sXBP1) transcription factor binds to the promoter region of Mymk gene during myogenesis. Overexpression of myomaker in IRE1-knockdown cultures rescues fusion defects. Finally, our results show that inducible deletion of IRE1 in satellite cells inhibits myoblast fusion and myofiber hypertrophy in response to functional overload. Collectively, our study demonstrates that IRE1 promotes myoblast fusion through sXBP1-mediated up-regulation in the gene expression of profusion molecules. Significance StatementMyoblast fusion is an essential step for regeneration and post-natal growth of skeletal muscle. We demonstrate that the activation of the IRE1/XBP1 arm of the unfolded protein response induces myoblast fusion through augmenting the gene expression of multiple profusion molecules, including myomaker. This study has identified a novel signaling axis that link ER stress-induced non-myogenic signaling pathway to myoblast fusion. Augmenting the activity of IRE1/XBP1 pathway could be a potential therapeutic strategy for various muscle degenerative diseases.

cell biology↗

bioRxiv2023

Molecular and network disruptions in neurodevelopment uncovered by single cell transcriptomics analysis of CHD8 heterozygous cerebral organoids

About 100 genes have been associated with significantly increased risks of autism spectrum disorders (ASD) with an estimate of [~]1000 genes that may be involved. The new challenge now is to investigate the molecular and cellular functions of these genes during neural and brain development, and then even more challenging, to link the altered molecular and cellular phenotypes to the ASD clinical manifestations. In this study, we use single cell RNA-seq analysis to study one of the top risk gene, CHD8, in cerebral organoids, which models early neural development. We identify 21 cell clusters in the organoid samples, representing non-neuronal cells, neural progenitors, and early differentiating neurons at the start of neural cell fate commitment. Comparisons of the cells with one copy of the CHD8 knockout and their isogenic controls uncover thousands of differentially expressed genes, which are enriched with function related to neural and brain development, with genes and pathways previously implicated in ASD, but surprisingly not for Schizophrenia and intellectual disability risk genes. The comparisons also find cell composition changes, indicating potential altered neural differential trajectories upon CHD8 reduction. Moreover, we find that cell-cell communications are affected in the CHD8 knockout organoids, including the interactions between neural and glial cells. Taken together, our results provide new data for understanding CHD8 functions in the early stages of neural lineage development and interaction.

genomics↗

bioRxiv2023

Cryo-EM structures of human SID-1 transmembrane family proteins and implications for their low-pH-dependent RNA transport activity

Human SIDT1 and SIDT2 are closely related members of the systemic RNA interference (RNAi)-defective (SID-1) transmembrane family. Both mediate RNA internalization and intracellular transport and are involved in various biological processes. However, the molecular basis of RNA uptake, especially for exogenous small RNAs, remains elusive. Here, we present the cryo-electron microscopy (cryo-EM) structures of human SIDT1 and SIDT2. Both structures reveal the overall architecture of a dimeric arrangement contributed by the {beta}-strand-rich extracellular domain (ECD) and the transmembrane domain (TMD) with 11 passes, highlighting the remarkable structural congruence. The in situ assays confirm that SIDT1 and SIDT2 exist as dimers or higher-order oligomers. We demonstrate that for both SIDT1 and SIDT2, the ECD binds small RNAs, such as dietary plant-derived miRNA, only under acidic conditions. In addition, RNA binding under low pH can trigger higher-order assembly of the ECD dimer, suggesting the potential importance of oligomerization during RNA uptake. Our results illustrate the molecular features of the conserved SID-1 family proteins to elucidate the mechanism of the low pH-dependent activation of RNA uptake mediated by SIDT1 and SIDT2. This study provides a promising understanding of the molecular basis of the nucleic acid delivery platform, which may potentially open new avenues for the design and optimization of RNA-based therapies.

biochemistry↗

bioRxiv2023

CellPolaris: Decoding Cell Fate through Generalization Transfer Learning of Gene Regulatory Networks

Cell fate changes are determined by gene regulatory network (GRN), a sophisticated system regulating gene expression in precise spatial and temporal patterns. However, existing methods for reconstructing GRNs suffer from inherent limitations, leading to compromised accuracy and application generalizability. In this study, we introduce CellPolaris, a computational system that leverages transfer learning algorithms to generate high-quality, cell-type-specific GRNs. Diverging from conventional GRN inference models, which heavily rely on integrating epigenomic data with transcriptomic information or adopt causal strategies through gene co-expression networks, CellPolaris employs high-confidence GRN sources for model training, relying exclusively on transcriptomic data to generate previously unknown cell-type-specific GRNs. Applications of CellPolaris demonstrate remarkable efficacy in predicting master regulatory factors and simulating in-silico perturbations of transcription factors during cell fate transition, attaining state-of-the-art performance in accurately predicting candidate key factors and outcomes in cell reprogramming and spermatogenesis with validated datasets. It is worth noting that, with a transfer learning framework, CellPolaris can perform GRN based predictions in all cell types even across species. Together, CellPolaris represents a significant advancement in deciphering the mechanisms of cell fate regulation, thereby enhancing the precision and efficiency of cell fate manipulation at high resolution.

bioinformatics↗

bioRxiv2023

Gut microbial genomes with paired isolates from China signify probiotic and cardiometabolic effects

The gut microbiome displays significant genetic differences between populations while systematic characterization of the genomic landscape of the gut microbiome in Asia populations remains limited. Here, we present the Chinese gut microbial reference (CGMR) set, comprising 101,060 high quality metagenomic assembled genomes (MAGs) of 3,707 non-redundant species paired with 1,376 live isolates from a national wide collection of 3,234 fecal samples across China. This improved reference set contains 987 novel species compared with existing resources worldwide. By associating MAGs with geographic and phenotypic characteristics, we observed regional-specific coexisting MAGs and MAGs with probiotic and cardiometabolic functionalities. We further conducted mice experiments to confirm the probiotic effects of two Faecalibacterium intestinalis isolates in alleviating constipation, the cardiometabolic influences of three Bacteroides fragilis_A isolates in obesity, and the functional potential of isolates from the two new species belonging to the genera Parabacteroides and Lactobacillus in host lipids metabolism. Our study not only expands the current microbial genomes with paired isolates but also demonstrates their probiotic and cardiometabolic effects on hosts, contributing to the mechanistic understanding of host-microbe interactions and the translation of microbiome-based personalized therapies.

microbiology↗

bioRxiv2023

Bio-inspired mineralization collagen induce fibrocartilage regeneration after tendon-bone injury by activating Gli1+Dkk3+ progenitor cells

A fibrocartilaginous connection between the tendon and bone, plays a critical role in transferring force from muscle to bone to enable joint movement. However, due to the high mechanical stress it experiences, the enthesis is vulnerable to injury and incapable of regenerating. The spatial relationship and functional basis of the principal components of the fibrocartilage - mineral and collagen - have not been clearly elucidated, which is a significant remaining gap in reconstructing complex architectures for promoting interface tissue regeneration. Here, using three-dimensional electron tomography imaging and high-resolution two-dimensional electron microscopy, we discover that mineral particles form a continuous cross-fibrillar phase within the fibrocartilage region. By developing a "floating mineralization" system, we fabricate a three-layer hydrogel that mimics the hierarchical nano- to micro-scale structure of tendon-bone interface (TBI). The middle layer is noteworthy for its resemblance to the nanostructure of fibrocartilage and its superior ability to induce mineralized fibrochondrogenesis in vitro. Based on motor function analysis, imaging diagnosis, histological staining, immunofluorescence staining, and biomechanics performance, we demonstrate that in situ transplantation of the gradient hydrogel achieved tendon-fibrocartilage-bone synchronous regeneration and result in 68% maximum mechanical recovery at 8-week postoperation. Single-cell RNA sequencing analysis reveals that a unique atlas of in situ stem/progenitor cells is generated during the TBI healing in vivo. Notably, the bio-inspired hydrogel microenvironment drived endogenous Gli1+Dkk3+ progenitor cells, playing a key role in TBI regeneration. Therefore, we have successfully decoded and reconstructed the nanostructure of fibrocartilage, which has great potential in TBI regeneration.

bioengineering↗

bioRxiv2023

Accurate somatic variant calling performance using Avidity Sequencing with Burning Rock OncoScreenTM Plus panel

BackgroundNext-generation sequencing (NGS) comprehensive genomic profiling panels provide targeted genome-wide detection of the somatic variant landscape of various cancer types. Recently, an innovative sequencing technology, Avidity Sequencing from Element Biosciences, has emerged to provide economical option for mid-throughput sequencing, with high quality (Q40). AimsThe aim of this study was to evaluate the performance characteristics of AVITI sequencing by avidity on detection of somatic variants from reference samples, and to compare the variant detection concordance between AVITI and NovaSeq sequencing platforms by evaluating the variant callings of 518 cancer-related genes using Burning Rocks OncoScreenTM Plus panel. MethodsContrived commercial reference control samples (harboring known variants) and clinical Formalin-Fixed Paraffin-Embedded tissue (FFPE) samples were examined to evaluate the variant detection performance of two sequencing platforms, with respects to Single Nucleotide Variant (SNV), Insertion-Deletion (Indel), Structure Variant (SV/Fusion), Copy Number Variation (CNV), Microsatellite Instability (MSI), and Tumor Mutation Burden (TMB). Variant specific QC metrics were developed to evaluate sequencing-level and variant calling level accuracy. All samples were processed utilizing the OncoScreenTM Plus assay, including library preparation and bioinformatics post sequencing data analysis. ResultsThe OncoScreenTM Plus assay is compatible with the AVITI system. Samples prepared with the OncoScreenTM Plus panel and sequenced on the AVITI system has successfully detected cancer related variants including SNV/Indels, SV/Fusion, CNVs, MSIs, and TMB, which were highly concordant with reference controls. In addition, the AVITI system produced a higher overall quality score, index assignment rate, mean target coverage, and lower optical duplication rate AVITI than NovaSeq system. ConclusionThe new sequencing technology Avidity from AVITI system can be applied seamlessly to current high-performance targeted oncology assays to reliably identify somatic variants in a flexible and cost-effective manner.

genomics↗

bioRxiv2023

ICG-Functionalized Gold Nanostars As An Effective Contrast Agent For Real-time Tumor Localization with Dynamic Optical Contrast Imaging (DOCI) and Enhanced Radiation Therapy

The primary management of head and neck squamous cell carcinoma relies on complete surgical resection of the tumor. However, the establishment of negative margin complete resection is often difficult given the devastating side effects of aggressive surgery and the anatomic proximity to vital structures. Positive margin status is associated with significantly decreased survival. Currently, surgeons determine where the tumor cuts are made, by palpating the edges of the tumor and using prior imaging. After a tumor is presumed to be removed in its entirety, the surrounding tissues are sampled by frozen section histologic pathology to ensure that no microscopic disease is left behind, the efficacy of which varies and is subject to sampling error. The methodology by which frozen sections are collected whether tumor bed driven or specimen driven can also alter margin outcome. Thus, improving intraoperative detection of tumor margins is key to optimizing treatment and outcomes. Our group has developed a possible solution for this unmet clinical need. We have previously designed Dynamic Optical Contrast Imaging (DOCI), a novel imaging modality that acquires temporally dependent measurements of tissue autofluorescence. Furthermore, we demonstrated that DOCI can distinguish HNSCC from adjacent healthy tissue with a high degree of accuracy. DOCI images are captured in real time and offer an operatively wide field of view. With the addition of ICG conjugated gold nanostars (GNS) we can improve DOCI image contrast between tumors vs normal tissues as well as use the GNS for CT imaging and radiotherapeutic treatment.

cancer biology↗

bioRxiv2023

A muscle hypertrophy-derived myokine reprograms the stromal vascular fractions differentiation towards thermogenic adipocytes in subcutaneous adipose tissue

Skeletal muscle plays a significant role in both local and systemic energy metabolism; however, the cross-talk between skeletal muscle and adipose tissue remains largely unexplored. In this study, we identify the HIF2-Bambi-Thbs4 axis as a critical driver of muscle hypertrophy and metabolic improvement. Deletion of Bambi induces muscle hypertrophy and oxidative switching, thereby enhancing local and systemic metabolism under conditions of rodent chow and high-fat diets (HFD). Other than the metabolic regulation of skeletal muscle hypertrophy, we hypothesize that a portion of this improvement may be attributed to the metabolic reprogramming of the stromal vascular fraction (SVFs) of iWAT, promoting the development of beige adipocytes. Leveraging multi-omics approaches, we establish Thbs4 as a newly identified, muscle hypertrophy-derived myokine that serves as an essential regulator of this metabolic reprogramming. Thbs4 is upregulated in skeletal muscle during hypertrophy and aerobic exercise, localizes to the iWAT membrane, and facilitates the transformation of white adipocytes into beige adipocytes under conditions such as cold exposure, muscle hypertrophy, or aerobic exercise. Moreover, overexpression of Thbs4 elevates its plasma levels and leads to the transformation of white to beige adipocytes, therefore offering long-term protection against HFD-induced metabolic disorders. Conversely, Thbs4 knockout (Thbs4-KO) disrupts the metabolic reprogramming of SVFs and exacerbates metabolic syndromes induced by an HFD, mirroring the observed decline in Thbs4 levels in aged mice. Therefore, our findings underscore Thbs4s potential as both a long-term metabolic protective factor and a therapeutic target for the treatment of metabolic disorders. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=197 HEIGHT=200 SRC="FIGDIR/small/558627v1_ufig1.gif" ALT="Figure 1"> View larger version (63K): org.highwire.dtl.DTLVardef@1178e6org.highwire.dtl.DTLVardef@1184d4eorg.highwire.dtl.DTLVardef@7b592aorg.highwire.dtl.DTLVardef@1b0b03_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIBambi, a direct target gene of HIF2 in skeletal muscle, when deleted, triggers muscle hypertrophy and the transformation of white into beige adipocytes, improving systemic energy metabolism. C_LIO_LIThe metabolic reprogramming of stromal vascular fractions (SVFs) contributes to the observed improvements in energy metabolism and adipocyte hyperplasia. C_LIO_LIThbs4, a novel myokine produced in skeletal muscle during hypertrophy and aerobic exercise, plays a key role in the transformation of white into beige adipocytes. C_LIO_LIOverexpression of Thbs4 provides enduring protection against high-fat diet (HFD)-induced metabolic disorders, demonstrating its potential as a therapeutic target. C_LIO_LIThbs4 deletion abrogates the beneficial metabolic reprogramming of SVFs and exacerbates HFD-induced metabolic syndromes, further underlining its crucial role in metabolic regulation. C_LI

physiology↗

bioRxiv2023

Multi-omics analysis reveals signatures of selection and loci associated with complex traits in pigs

Selection signatures that contribute to phenotypic diversity, especially morphogenesis in pigs, remain to be further elucidated. To reveal the regulatory role of genetic variations in phenotypic differences between Eastern and Western pig breeds, we performed a systematic analysis based on seven high-quality de novo assembled genomes, 1,081 resequencing data representing 78 domestic breeds, 162 methylomes, and 162 transcriptomes of skeletal muscle from Tongcheng (Eastern) and Landrace (Western) pigs at 27 developmental stages. Selective sweep uncovers different genetic architectures behind divergent selection directions for the Eastern and Western breeds. Notably, two loci showed functional alterations by almost fixed missense mutations. By integrating time-course transcriptome and methylome, we revealed differences in developmental timing during myogenesis between Eastern and Western breeds. Genetic variants under artificial selection have critical regulatory effects on progression patterns of heterochronic genes like GHSR and BDH1, by the interaction of local DNA methylation status, particularly during embryonic development. Altogether, our work not only provides valuable resources for understanding pig complex traits, but also contributes to human biomedical research.

genomics↗

bioRxiv2023

Comparative single-cell regulome reveals evolutionary innovations in neural progenitor cells during primate corticogenesis

The cellular and genetic mechanism underlying the human-specific features of cortex development remains unclear. We generated a cell-type resolved atlas of transcriptome and regulome of the developing macaque and mouse prefrontal cortex, and conducted evolutionary analyses with the published complementary human data. We discovered a primate-specific expansion of two neural progenitor subclasses, glia-committed radial glia (RG) and truncated RG. Specifically, the human neural progenitors show extensive transcriptional rewiring in the growth factor and extracellular matrix pathways. Expression of the human-specific progenitor marker ITGA2 in the cortex of fetal mouse promotes progenitor proliferation and an increased upper-layer neuron proportion. We demonstrate that these transcriptional divergences are primarily driven by the activity changes of the distal regulatory elements in the genome. Markedly, the chromatin regions with human-gained accessibility enrich the human-fixed sequence changes, as well as sequence polymorphisms associated with intelligence and neuropsychiatric disorders. Our results uncover evolutionary innovations in neural progenitors and gene regulatory mechanism during primate cortex evolution.

evolutionary biology↗

bioRxiv2023

Massively parallel in vivo Perturb-seq reveals cell type-specific transcriptional networks in cortical development

Systematic analysis of gene function across diverse cell types in vivo is hindered by two challenges: obtaining sufficient cells from live tissues and accurately identifying each cells perturbation in high-throughput single-cell assays. Leveraging AAVs versatile cell type tropism and high labeling capacity, we expanded the resolution and scale of in vivo CRISPR screens: allowing phenotypic analysis at single-cell resolution across a multitude of cell types in the embryonic brain, adult brain, and peripheral nervous system. We undertook extensive tests of 86 AAV serotypes, combined with a transposon system, to substantially amplify labeling and accelerate in vivo gene delivery from weeks to days. Using this platform, we performed an in utero genetic screen as proof-of-principle and identified pleiotropic regulatory networks of Foxg1 in cortical development, including Layer 6 corticothalamic neurons where it tightly controls distinct networks essential for cell fate specification. Notably, our platform can label >6% of cerebral cells, surpassing the current state-of-the-art efficacy at <0.1% (mediated by lentivirus), and achieve analysis of over 30,000 cells in one experiment, thus enabling massively parallel in vivo Perturb-seq. Compatible with various perturbation techniques (CRISPRa/i) and phenotypic measurements (single-cell or spatial multi-omics), our platform presents a flexible, modular approach to interrogate gene function across diverse cell types in vivo, connecting gene variants to their causal functions.

neuroscience↗

bioRxiv2023

Depleting glioblastoma cells of very long-chain acyl-CoA synthetase 3 (ACSVL3) produces metabolic alterations in non-lipid pathways

Knockout (KO) of the fatty acid-activation enzyme very long-chain acyl-CoA synthetase 3 (ACSVL3; SLC27A3) in U87MG glioblastoma cells reduced their malignant growth properties both in vitro and in xenografts. These U87-KO glioma cells grew at a slower rate, became adherence-dependent, and were less invasive than parental U87 cells. U87-KO cells produced fewer, slower-growing subcutaneous and intracranial tumors when implanted in NOD-SCID mice. Thus, depleting U87MG cells of ACSVL3 restored these cells to a phenotype more like that of normal astrocytes. To understand the mechanisms underlying these beneficial changes, we investigated several possibilities, including the effects of ACSVL3 depletion on carbohydrate metabolism. Proteomic and metabolomic profiling indicated that ACSVL3 KO produced changes in glucose and energy metabolism. Even though protein levels of glucose transporters GLUT1 and GLUT3 were reduced by KO, cellular uptake of labeled 2-deoxyglucose was unaffected. Glucose oxidation to CO2 was reduced nearly 7-fold by ACSVL3 depletion, and the cellular glucose level was 25% higher in KO cells. Glycolytic enzymes were upregulated by KO, but metabolic intermediates were essentially unchanged. Surprisingly, lactate production and the levels of lactate dehydrogenase isozymes LDHA and LDHB were elevated by ACSVL3 KO. The activity of the pentose phosphate pathway was found to be lower in KO cells. Citric acid cycle enzymes, electron transport chain complexes, and ATP synthase protein levels were all reduced by ACSVL3 depletion. Mitochondria were elongated in KO cells, but had a more punctate morphology in U87 cells. The mitochondrial potential was unaffected by lack of ACSVL3. We conclude that the beneficial effects of ACSVL3 depletion in human glioblastoma cells may result in part from alterations in diverse metabolic processes that are not directly related to role(s) of this enzyme in fatty acid and/or lipid metabolism. (Supported by NIH 5R01NS062043 and KKI institutional funds.)

biochemistry↗

bioRxiv2023

Decoding genetic architecture of dog complex traits by constructing fine-scale genomic ancestry of admixture

Domestic animals and plants exhibit remarkable phenotypic diversity in terms of morphology, behavior, and physiology, which can be attributed to the complex interbreeding process of various breeds and artificial selection. Here we develop a method that can efficiently construct fine-scale interbreeding history of local segments along the genome. Since ancestral breeds usually exhibit diverse phenotypes, the method provides a valuable approach for unraveling the genetic architecture of complex traits in admixed breeds. Simulated data demonstrates that the method performs well, even in scenarios involving complex interbreeding with up to 19 ancestral breeds. The method is applied to analyze three mixed dog breeds, Irish Wolfhound, Giant Schnauzer, and Miniature Schnauzer, representing instances of body-size enlargement and miniaturization. Numerous novel ancestor breed-specific genes determining body size are identified, including FGFR2, WDR11, and FARS2. We also validate genes reported in previous GWAS or genomic sweep scans, such as LCORL, STC2, NPR2, and FGF4. These findings highlight the validity of the method as a valuable tool for investigating the genetic basis underlying ancestry-specific traits in domestic animals and plants with complex interbreeding histories.

evolutionary biology↗

bioRxiv2023

Magnetically Powered Microwheel Thrombolysis of Occlusive Thrombi in Zebrafish

Tissue plasminogen activator (tPA) is the only FDA approved treatment for ischemic stroke but carries significant risks, including major hemorrhage. Additional options are needed, especially in small vessel thrombi which account for [~]25% of ischemic strokes. We have previously shown that tPA-functionalized colloidal microparticles can be assembled into microwheels ({micro}wheels) and manipulated under the control of applied magnetic fields to enable rapid thrombolysis of fibrin gels in microfluidic models of thrombosis. Providing a living microfluidic analog, transparent zebrafish larvae have a highly conserved coagulation cascade that enables studies of hemostasis and thrombosis in the context of intact vasculature, clotting factors, and blood cells. Here we show that tPA-functionalized {micro}wheels can perform rapid and targeted recanalization in vivo. This effect requires both tPA and {micro}wheels, as minimal to no recanalization is achieved with tPA alone, {micro}wheels alone, or tPA-functionalized microparticles in the absence of a magnetic field. We evaluated tPA-{micro}wheels in CRISPR-generated plasminogen (plg) heterozygous and homozygous mutants and confirmed that tPA-{micro}wheels are dose-dependent on plasminogen for lysis. We have found that magnetically powered {micro}wheels as a targeted tPA delivery system are dramatically more efficient at plasmin-mediated thrombolysis than systemic delivery in vivo. Further development of this system in fish and mammalian models could enable a less invasive strategy for alleviating ischemia that is safer than directed thrombectomy or systemic infusion of tPA.

bioengineering↗

bioRxiv2023

Developmental priming of cancer susceptibility

DNA mutations are necessary drivers of cancer, yet only a small subset of mutated cells go on to cause the disease. To date, the mechanisms that determine which rare subset of cells transform and initiate tumorigenesis remain unclear. Here, we take advantage of a unique model of intrinsic developmental heterogeneity (Trim28+/D9) and demonstrate that stochastic early life epigenetic variation can trigger distinct cancer-susceptibility states in adulthood. We show that these developmentally primed states are characterized by differential methylation patterns at typically silenced heterochromatin, and that these epigenetic signatures are detectable as early as 10 days of age. The differentially methylated loci are enriched for genes with known oncogenic potential. These same genes are frequently mutated in human cancers, and their dysregulation correlates with poor prognosis. These results provide proof-of-concept that intrinsic developmental heterogeneity can prime individual, life-long cancer risk.

cancer biology↗

bioRxiv2023

Combining Bulk and Single-Cell RNA Sequencing Data to Identify RNA methylation and Autophagy-Related Signatures in Patients with Chronic Obstructive Pulmonary Disease

BackgroundChronic Obstructive Pulmonary Disease (COPD) is a heterogeneous lung condition associated with RNA methylation and autophagy. However, the specific autophagy-related genes and RNA methylation regulators involved in COPD development remain unknown. MethodsWe analyzed COPD and non-COPD patients datasets obtained from the Gene Expression Omnibus database, including Tissue Sequencing Transcriptome (bulk-seq) and single-cell sequencing (scRNA-seq) data. Differentially expressed genes (DEGs) were identified through differential genetic analysis using non-COPD bulk-seq data as the control group and COPD samples were used as the experimental group. Animal experiments were conducted to validate the expression of key genes. COPD model mice were exposed to smoke for four months, and lung function and histopathological changes were assessed. The mRNA and protein expression levels of FTO, IGF2BP2, DDIT3, DNAJB1, and YTHDF3 were measured using RT-qPCR and Western blotting, respectively. ResultsWe identified FTO, IGF2BP2, and YTHDF3 as key methylation genes, along with autophagy hub genes DDIT3 and DNAJB1. Animal experiments showed significantly increased mRNA and protein levels of FTO, YTHDF3 and DNAJB1 and significantly decreased levels of IGF2BP2 in lung tissue of COPD mice compared to the control group. ConclusionOur findings suggest that DDIT3 and DNAJB1 as autophagy hub genes, along with FTO, IGF2BP2 and YTHDF3 as RNA methylation genes, may play crucial roles in the development of COPD. These findings, supported by bulk-seq and scRNA-seq data, contribute novel genetic evidence for understanding the epigenetics of COPD.

cell biology↗

bioRxiv2023

Replay-triggered Brain-wide Activation in Humans

The consolidation of discrete experiences into a coherent narrative shape our cognitive map, providing a structured mental representation of our experiences. Neural replay, by fostering crucial hippocampal-cortical dialogue, is thought to be pivotal in this process. However, the brain-wide engagement coinciding with replay bursts remains largely unexplored. In this study, by employing simultaneous EEG-fMRI, we capture both the spatial and temporal dynamics of replay. We find that during mental simulation, the strength of on-task replay, as detected via EEG, correlates with heightened fMRI activity in the hippocampus and medial prefrontal cortex. Intriguingly, increased replay strength also enhances the functional connectivity between the hippocampus and the default mode network, a set of brain regions key to representing cognitive map. Furthermore, during the post-learning resting state, we observed a positive association between increased task-related reactivation, hippocampal activity, and augmented connectivity to the entorhinal cortex. Our findings elucidate the neural mechanism of human replay in both time and space, providing novel insights into dynamics of replay and associated brain-wide activation.

neuroscience↗