Biology subjects

Lin, C.-Y.

Publications and source records attributed to Lin, C.-Y..

At least 37 records · Page 2Linked to original sources

bioRxiv2024

Tricuspid valve maladaptation in sheep with biventricular heart failure: The posterior and septal leaflets

Tricuspid valve leaflets are dynamic tissues that can respond to altered biomechanical and hemodynamic loads. Each leaflet has unique structural and mechanical properties, leading to differential in vivo strains. We hypothesized that these intrinsic differences drive heterogeneous, disease-induced remodeling between the leaflets. Although we previously reported significant remodeling changes in the anterior leaflet, the responses among the other two leaflets have not been reported. Using a sheep model of biventricular heart failure, we compared the remodeling responses between all tricuspid leaflets. Our results show that the anterior leaflet underwent the most significant remodeling, while the septal and posterior leaflets exhibited similar but less pronounced changes. We found several between-leaflet differences in key structural and mechanical metrics that have been shown to contribute to valvular dysfunction. These findings underscore the need to consider leaflet-specific remodeling to fully understand tricuspid valve dysfunction and to develop targeted therapies for its treatment and more accurate computational models. STATEMENT OF SIGNIFICANCEOur study is significant as it advances our understanding of tricuspid valve remodeling by providing a comprehensive analysis of all three leaflets in a sheep model of biventricular heart failure. Unlike prior works that focused primarily on the anterior leaflet or generalized leaflet changes, we integrated morphological, histological, immunohistochemistry, biaxial mechanical testing, and two-photon microscopy to quantify differences between all three tricuspid valve leaflets (anterior, posterior, and septal) across multiple functional scales. This comprehensive approach highlights the unique remodeling response of each leaflet. Our findings offer critical insights for developing targeted therapeutic strategies and improving computational models of disease progression. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=119 SRC="FIGDIR/small/613284v2_ufig1.gif" ALT="Figure 1"> View larger version (40K): org.highwire.dtl.DTLVardef@1e8efaforg.highwire.dtl.DTLVardef@1cfee04org.highwire.dtl.DTLVardef@136956org.highwire.dtl.DTLVardef@68c488_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioengineering↗

bioRxiv2024

StomaVision: stomatal trait analysis through deep learning

StomaVision is an automated tool designed for high-throughput detection and measurement of stomatal traits, such as stomatal number, pore size, and closure rate. It provides insights into plant responses to environmental cues, streamlining the analysis of micrographs from field-grown plants across various species, including monocots and dicots. Enhanced by a novel collection method that utilizes video recording, StomaVision increases the number of captured images for robust statistical analysis. Accessible via an intuitive web interface at and available for local use in a containerized environment at , this tool ensures long-term usability by minimizing the impact of software updates and maintaining functionality with minimal setup requirements. The application of StomaVision has provided significant physiological insights, such as variations in stomatal density, opening rates, and total pore area under heat stress. These traits correlate with critical physiological processes, including gas exchange, carbon assimilation, and water use efficiency, demonstrating the tools utility in advancing our understanding of plant physiology. The ability of StomaVision to identify differences in responses to varying durations of heat treatment highlights its value in plant science research. Plain language summaryStomaVision is a tool that automatically counts and measures tiny openings on plant leaves, helping us learn how plants deal with their surroundings. It is easy to use and works well with various plant species. This tool helps scientists see how plants change under stress, making plant research easier and more accurate.

plant biology↗

bioRxiv2023

Neratinib Synergizes with Trastuzumab Antibody Drug Conjugate or with Vinorelbine to Treat HER2 Mutated Breast Cancer Patient Derived Xenografts and Organoids.

HER2 (ERBB2) is a major therapeutic drug target in breast cancer and The Cancer Genome Atlas (TCGA) Breast Cancer project and other studies have identified HER2 activating mutations in breast cancers without HER2 gene amplification. HER2 activating mutations occur in 2-5% of metastatic breast cancer patients (MBC), and clinical trials have shown that the irreversible pan-HER tyrosine kinase inhibitor, neratinib, produces a 31-40% clinical benefit rate for HER2 mutated MBC patients. We developed breast cancer patient-derived xenografts (PDX) from ER+, HER2 mutated MBC patients and used them to test neratinib-based drug combinations. Using organoid culture of these PDX breast cancer cells, we performed rapid, high-throughput ex vivo screening assays to test novel drug combinations. These organoid culture experiments identified drug synergy with the neratinib plus ado-trastuzumab emtansine (T-DM1) and neratinib plus vinorelbine combinations and we validated these results with in vivo PDX experiments. Statement of SignificancePDXs are a ready source of human cancer organoids, and with thousands of PDXs already available worldwide, PDX derived organoids (PDxOs) can dramatically accelerate cancer drug testing. This strategy of PDxO drug testing is particularly useful for rare cancer subtypes or mutations to identify the most promising treatment strategies for clinical trials testing.

cancer biology↗

bioRxiv2023

Chromosome-level genome assemblies of two hemichordates provide new insights into deuterostome origin and chromosome evolution

Deuterostomes are an animal superphylum that includes Hemichordata and Echinodermata (together Ambulacraria) and Chordata. The diversity of deuterostome body plans has made it challenging to reconstruct their ancestral condition and to decipher the genetic changes that drove the diversification of deuterostome lineages. Here, we generate chromosome-level genome assemblies of two hemichordate species, Ptychodera flava and Schizocardium californicum, and use comparative genomic approaches to infer the chromosomal architecture of the deuterostome common ancestor and delineate lineage-specific chromosomal modifications. We show that hemichordate chromosomes (1N=23) exhibit remarkable chromosome-scale macrosynteny when compared to other deuterostomes, and can be derived from 24 deuterostome ancestral linkage groups (ALGs). These deuterostome ALGs in turn match previously inferred bilaterian ALGs, consistent with a relatively short transition from the last common bilaterian ancestor to the origin of deuterostomes. Based on this deuterostome ALG complement, we deduced chromosomal rearrangement events that occurred in different lineages. For example, a fusion-with-mixing event produced an Ambulacraria-specific ALG that subsequently split into two chromosomes in extant hemichordates, while this homologous ALG further fused with another chromosome in sea urchins. Orthologous genes distributed in these rearranged chromosomes are enriched for functions in various developmental processes. We found that the deeply conserved Hox clusters are located in highly rearranged chromosomes but have lower densities of transposable elements within the clusters. We also provide evidence that the deuterostome-specific pharyngeal gene cluster was established via the combination of three pre-assembled microsyntenic blocks. We suggest that since chromosomal rearrangement events and formation of new gene clusters may change the regulatory controls of developmental genes, these events may have contributed to the evolution of diverse body plans among deuterostomes.

evolutionary biology↗

bioRxiv2023

Insights into RAG evolution from the identification of "missing link" family A RAGL transposons

A series of "molecular domestication" events are thought to have converted an invertebrate RAG-like (RAGL) transposase into the RAG1-RAG2 (RAG) recombinase, a critical enzyme for adaptive immunity in jawed vertebrates. The timing and order of these events is not well understood, in part because of a dearth of information regarding the invertebrate RAGL-A transposon family. In contrast to the abundant and divergent RAGL-B transposon family, RAGL-A most closely resembles RAG and is represented by a single orphan RAG1-like (RAG1L) gene in the genome of the hemichordate Ptychodera flava (PflRAG1L-A). Here, we provide evidence for the existence of complete RAGL-A transposons in the genomes of P. flava and several echinoderms. The predicted RAG1L-A and RAG2L-A proteins encoded by these transposons intermingle sequence features of jawed vertebrate RAG and RAGL-B transposases, leading to a prediction of DNA binding, catalytic, and transposition activities that are a hybrid of RAG and RAGL-B. Similarly, the terminal inverted repeats (TIRs) of the RAGL-A transposons combine features of both RAGL-B transposon TIRs and RAG recombination signal sequences. Unlike all previously described RAG2L proteins, PflRAG2L-A and echinoderm RAG2L-A contain an acidic hinge region, which we demonstrate is capable of efficiently inhibiting RAG-mediated transposition. Our findings provide evidence for a critical intermediate in RAG evolution and argue that certain adaptations thought to be specific to jawed vertebrates (e.g., the RAG2 acidic hinge) actually arose in invertebrates, thereby focusing attention on other adaptations as the pivotal steps in the completion of RAG domestication in jawed vertebrates.

evolutionary biology↗

bioRxiv2023

A Novel Genome Optimization Tool for Chromosome-Level Assembly across Diverse Sequencing Techniques

This paper introduces a novel genome assembly optimization tool named LOCLA, which stands for "Local Optimization for Chromosome-Level Assembly". It identifies reads and contigs aligned locally with high quality on gap flanks or scaffold boundaries of draft assemblies for gap filling and scaffold connection. LOCLA applies to both de novo and reference-based assemblies. It can also utilize reads produced by diverse sequencing techniques, e.g., 10x Genomics (10xG) Linked-Reads, and PacBio HiFi reads. We validated LOCLA on three human samples and one non-model organism. For the first two human samples, LLD0021C and CHM13, we generated de novo draft assemblies from 10xG Linked-Reads. On LLD0021C, LOCLA improves the draft assembly by adding 23.3 million bases using only 10xG Linked-Reads. These additional bases cover 28,746 protein-coding regions, particularly in pericentromeric and telomeric regions. On the CHM13 sample, we took 10xG Linked-Reads and PacBio HiFi reads as input. As a result, LOCLA added 46.2 million bases to the draft assembly. The increased content enables us to identify genes linked to complex diseases (e.g., ARHGAP11A) and critical biological pathways. We created two reference-guided draft assemblies on the third human sample, HG002, using contigs assembled from PacBio HiFi reads. LOCLA enhances the two draft assemblies by recovering 27.9 million bases (22.26%) and 35.7 million bases (30.93%) of the sequences discarded by the reference-guided assembly tool. The results indicate the robustness of LOCLAs contig detection algorithm on gap flanks. Furthermore, we show that 95% of the sequences filled in by LOCLA have over 80% accuracy compared with the HG002 reference genome published by the Human Pan-genome Reference Consortium. On the non-model organism, LOCLA enhanced the genome assembly of Bruguiera sexangula (JAHLGP000000000) by decreasing 41.4% of its gaps and raising the Benchmarking Universal Single-Copy Orthologs (BUSCO) analysis score to 98.10%. LOCLA can optimize de novo and reference-guided assemblies using varied sequencing reads. The final assemblies produced by LOCLA have improved in both quantity and quality. The increased gene content may provide a valuable resource in advancing personalized medicine.

genomics↗

bioRxiv2023

Synergistic Binding of the Halide and Cationic Prime Substrate of the L-Lysine 4-Chlorinase, BesD, in Both Ferrous and Ferryl States

An aliphatic halogenase requires four substrates: 2-oxoglutarate (2OG), halide (Cl- or Br-), the halogenation target ("prime substrate"), and dioxygen. In well-studied cases, the three non-gaseous substrates must bind to activate the enzymes Fe(II) cofactor for efficient capture of O2. Halide, 2OG, and (lastly) O2 all coordinate directly to the cofactor to initiate its conversion to a cis-halo-oxo-iron(IV) (haloferryl) complex, which abstracts hydrogen (H*) from the non-coordinating prime substrate to enable radicaloid carbon-halogen coupling. We dissected the kinetic pathway and thermodynamic linkage in binding of the first three substrates of the O_SCPLOWLC_SCPLOW-lysine 4-chlorinase, BesD. After 2OG adds, subsequent coordination of the halide to the cofactor and binding of cationic O_SCPLOWLC_SCPLOW-Lys near the cofactor are associated with strong heterotropic cooperativity. Progression to the haloferryl intermediate upon addition of O2 does not trap the substrates in the active site and, in fact, markedly diminishes cooperativity between halide and O_SCPLOWLC_SCPLOW-Lys. The surprising lability of the BesD*[Fe(IV)=O]*Cl*succinate*O_SCPLOWLC_SCPLOW-Lys complex engenders pathways for decay of the haloferryl intermediate that do not result in O_SCPLOWLC_SCPLOW-Lys chlorination, especially at low chloride concentrations; one identified pathway involves oxidation of glycerol. The mechanistic data imply that (i) BesD may have evolved from a hydroxylase ancestor either relatively recently or under weak selective pressure for efficient chlorination and (ii) that acquisition of its activity may have involved the emergence of linkage between O_SCPLOWLC_SCPLOW-Lys binding and chloride coordination following loss of the anionic protein-carboxylate iron ligand present in extant hydroxylases.

biochemistry↗

bioRxiv2023

Expansion of Disease Specific Cardiac Macrophages in Immune Checkpoint Inhibitor Myocarditis

BackgroundImmune checkpoint inhibitors (ICIs), antibodies targeting PD-1/PD-L1 or CTLA4 have revolutionized cancer management but are associated with devastating immune-related adverse events (irAEs) including myocarditis. The main risk factor for ICI myocarditis is the use of combination PD-1 and CTLA4 inhibition. ICI-myocarditis is often fulminant and is pathologically characterized by myocardial infiltration of T lymphocytes and macrophages. While much has been learned regarding the role of T-cells in ICI-myocarditis, little is understood regarding the identity, transcriptional diversity, and functions of infiltrating macrophages. MethodsWe employed an established murine ICI myocarditis model (Ctla4+/-Pdcd1-/- mice) to explore the cardiac immune landscape using single-cell RNA-sequencing, immunostaining, flow cytometry, in situ RNA hybridization and molecular imaging and antibody neutralization studies. ResultsWe observed marked increases in CCR2+ monocyte-derived macrophages and CD8+ T-cells in this model. The macrophage compartment was heterogeneous and displayed marked enrichment in an inflammatory CCR2+ subpopulation highly expressing Cxcl9, Cxcl10, Gbp2b, and Fcgr4 that originated from CCR2+ monocytes. Importantly, a similar macrophage population expressing CXCL9, CXCL10, and CD16 (human homologue of mouse FcgR4) was found selectively expanded in patients with ICI myocarditis compared to other forms of heart failure and myocarditis. In silico prediction of cell-cell communication suggested interactions between T-cells and Cxcl9+Cxcl10+ macrophages via IFN-{gamma} and CXCR3 signaling pathways. Depleting CD8+T-cells, macrophages, and blockade of IFN-{gamma} signaling blunted the expansion of Cxcl9+Cxcl10+macrophages in the heart and attenuated myocarditis suggesting that this interaction was necessary for disease pathogenesis. ConclusionThese data demonstrate that ICI-myocarditis is associated with the expansion of a specific population of IFN-{gamma} induced inflammatory macrophages and suggest the possibility that IFN-{gamma} blockade may be considered as a treatment option for this devastating condition.

immunology↗

bioRxiv2023

Sex- and Age-dependent Skin Mechanics - A Detailed Look in Mice

Skin aging is of immense societal and, thus, scientific interest. Because mechanics play a critical role in skins function, a plethora of studies have investigated age-induced changes in skin mechanics. Nonetheless, much remains to be learned about the mechanics of aging skin. This is especially true when considering sex as a biological variable. In our work, we set out to answer some of these questions using mice as a model system. Specifically, we combined mechanical testing, histology, collagen assays, and two-photon microscopy to identify age- and sex-dependent changes in skin mechanics and to relate them to structural, microstructural, and compositional factors. Our work revealed that skin stiffness, thickness, and collagen content all decreased with age and were sex dependent. Interestingly, sex differences in stiffness were age induced. We hope our findings not only further our fundamental understanding of skin aging but also highlight both age and sex as important variables when conducting studies on skin mechanics.

biophysics↗

bioRxiv2023

Measuring and Modeling Macrophage Growth using a Lab-on-CMOS Capacitance Sensing Microsystem

We report on the use of a lab-on-CMOS biosensor platform for quantitatively tracking the growth of RAW 264.7 murine Balb/c macrophages. We show that macrophage growth over a wide sensing area correlates linearly with an average capacitance growth factor resulting from capacitance measurements at a plurality of electrodes dispersed in the sensing area. We further show a temporal model that captures the cell evolution in the area of interest over long periods (e.g., 30 hours). The model links the cell numbers and the average capacitance growth factor associated with the sensing area to describe the observed growth kinetics.

bioengineering↗

bioRxiv2023

Divergent Proteome Reactivity Influences Arm-Selective Activation of Pharmacological Endoplasmic Reticulum Proteostasis Regulators

Pharmacological activation of the activating transcription factor 6 (ATF6) arm of the Unfolded Protein Response (UPR) has proven useful for ameliorating proteostasis deficiencies in a variety of etiologically diverse diseases. Previous high-throughput screening efforts identified the small molecule AA147 as a potent and selective ATF6 activating compound that operates through a mechanism involving metabolic activation of its 2-amino-p-cresol substructure affording a quinone methide, which then covalently modifies a subset of ER protein disulfide isomerases (PDIs). Intriguingly, another compound identified in this screen, AA132, also contains a 2-amino-p-cresol moiety; however, this compound showed less transcriptional selectivity, instead globally activating all three arms of the UPR. Here, we show that AA132 activates global UPR signaling through a mechanism analogous to that of AA147, involving metabolic activation and covalent PDI modification. Chemoproteomic-enabled analyses show that AA132 covalently modifies PDIs to a greater extent than AA147. Paradoxically, activated AA132 reacts slower with PDIs, indicating it is less reactive than activated AA147. This suggests that the higher labeling of PDIs observed with activated AA132 can be attributed to its lower reactivity, which allows this activated compound to persist longer in the cellular environment prior to quenching by endogenous nucleophiles. Collectively, these results suggest that AA132 globally activates the UPR through increased engagement of ER PDIs. Consistent with this, reducing the cellular concentration of AA132 decreases PDI modifications and allows for selective ATF6 activation. Our results highlight the relationship between metabolically activatable-electrophile stability, ER proteome reactivity, and the transcriptional response observed with the enaminone chemotype of ER proteostasis regulators, enabling continued development of next-generation ATF6 activating compounds.

biochemistry↗

bioRxiv2022

The role of the cerebellum in learning to predict reward: evidence from cerebellar ataxia

Recent findings in animals have challenged the traditional view of the cerebellum solely as the site of motor control, suggesting that the cerebellum may also be important for learning to predict reward from trial-and-error feedback. Yet, evidence for the role of the cerebellum in reward learning in humans is lacking. Moreover, open questions remain about which specific aspects of reward learning the cerebellum may contribute to. Here we address this gap through an investigation of multiple forms of reward learning in individuals with cerebellum dysfunction, represented by cerebellar ataxia cases. Nineteen participants with cerebellar ataxia and 57 age- and sex-matched healthy controls completed two separate tasks that required learning about reward contingencies from trial-and-error. To probe the selectivity of reward learning processes, the tasks differed in their underlying structure: while one task measured incremental reward learning ability alone, the other allowed participants to use an alternative learning strategy based on episodic memory alongside incremental reward learning. We found that individuals with cerebellar ataxia were profoundly impaired at reward learning from trial-and-error feedback on both tasks, but retained the ability to learn to predict reward based on episodic memory. These findings provide evidence from humans for a specific and necessary role for the cerebellum in incremental learning of reward associations based on reinforcement. More broadly, the findings suggest that alongside its role in motor learning, the cerebellum likely operates in concert with the basal ganglia to support reinforcement learning from reward.

neuroscience↗

bioRxiv2022

Insights into deuterostome evolution from the biphasic transcriptional programmes of hemichordates

Evolutionary history of deuterostomes remains unsolved and is intimately related to the origin of chordates. Among deuterostomes, hemichordates and echinoderms (collectively called Ambulacraria) are sister groups of chordates. Comparative studies involving these three groups provide valuable insights into deuterostome evolution. Indirect developing hemichordates produce planktonic larvae that bear resemblance to echinoderm larvae before undergoing metamorphosis into an adult body plan with anteroposterior polarity homologous to that of chordates. Therefore, understanding the developmental processes of indirect-developing hemichordates can help understand the evolution of deuterostomes and the origins of chordates. In this study, we analysed the transcriptomes and chromatin accessibility of multiple developmental stages of the indirect-developing hemichordate Ptychodera flava and discovered that it exhibits a biphasic developmental program controlled by distinct sets of transcription factors and their corresponding regulatory elements. Comparative analyses of transcriptomes and network analyses revealed that the gastrula transcriptome is relatively ancient, and the TFs orchestrating its gene expression are highly interconnected in networks of cis-regulatory interactions. Comparing the developmental transcriptomes of hemichordates, echinoderms, and amphioxus, revealed high conservation of gene expression during gastrulation that extends to the neurula stages of amphioxus, along with remarkable similarity in larval transcriptomes across the three species. Additionally, we show that P. flava possesses conserved interactions of transcription factors necessary for the development of echinoderm endomesoderm and chordate axial mesoderm, including conserved cis-regulatory elements of the FoxA transcription factor that is central to the two networks. These findings suggest the existence of a deuterostome phylotypic stage during gastrulation governed by gene regulatory networks with conserved cis-regulatory interactions. Conversely, integration of gene expression data with synteny data revealed that gene expression recapitulates the independent evolutionary history of the Ancestral Linkage Groups that underwent rearrangements in each deuterostome lineage, suggesting a potential role of genome rearrangement during the evolution of larval strategies in hemichordates and deuterostome body plans.

evolutionary biology↗

bioRxiv2022

SMN promotes mitochondrial metabolic maturation during myogenesis by regulating the MYOD-miRNA axis.

Spinal muscular atrophy (SMA) is a congenital neuromuscular disease caused by the mutation or deletion of survival motor neuron 1 (SMN1) gene. Although the primary cause of progressive muscle atrophy in SMA has classically been considered the degeneration of motor neurons, recent studies have indicated a skeletal muscle-specific pathological phenotype such as impaired mitochondrial function and enhanced cell death. Here we found that the downregulation of SMN causes mitochondrial dysfunction and subsequent cell death in in vitro models of skeletal myogenesis with both a murine C2C12 cell line and human induced pluripotent stem cells. During myogenesis, SMN binds to the genome upstream of the transcriptional start sites of MYOD1 and microRNA (miR)-1 and -206. Accordingly, the loss of SMN downregulates these miRs, whereas supplementation of the miRs recovers the mitochondrial function, cell survival and myotube formation of SMN-deficient C2C12, indicating the SMN-miR axis is essential for myogenic metabolic maturation. Additionally, introduction of the miRs into ex vivo muscle stem cells derived from {Delta}7-SMA mice caused myotube formation and muscle contraction. In conclusion, our data revealed novel transcriptional roles of SMN during myogenesis, providing an alternative muscle-oriented therapeutic strategy for SMA patients. HighlightsO_LIReduced SMN causes mitochondrial dysregulation in myogenic cells. C_LIO_LIReduced SMN downregulates miR-1 and miR-206 expression in myogenic cells. C_LIO_LISMN protein binds to the genome upstream of MYOD1, miR-1 and miR-206. C_LIO_LImiR-1 and miR-206 are sufficient to improve skeletal muscle function in an SMA model. C_LI

cell biology↗

bioRxiv2022

Peptide-based drug predictions for cancer therapy using deep learning

BackgroundTherapeutic drugs used in cancer treatment have ineffectiveness and resistance to drug action problems. Anticancer peptides (ACPs) are selective and toxic to cancer cells and quickly produced. Thus, ACPs can be a satisfactory substitute for therapeutic drugs. We developed AI4ACP, a user-friendly web-server ACP predictor that can predict the anticancer property of query peptides, thus promoting the discovery of peptides with anticancer activity. ResultOur results revealed that the performance of our ACP predictor trained using the new ACP collection was superior to that of the available high-performance ACP predictors. ConclusionsAI4ACP is a user-friendly web-server ACP predictor that can be used to determine whether a query sequence is an ACP. This tool can be beneficial for drug development for cancer treatment. AI4ACP is freely accessible at https://axp.iis.sinica.edu.tw/AI4ACP/

cancer biology↗

bioRxiv2022

In vivo correction of cystic fibrosis mediated by PNA nanoparticles

Cystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. We sought to correct the multiple organ dysfunction of the F508del CF-causing mutation using systemic delivery of peptide nucleic acid gene editing technology mediated by biocompatible polymeric nanoparticles. We confirmed phenotypic and genotypic modification in vitro in primary nasal epithelial cells from F508del mice grown at air-liquid interface and in vivo in F508del mice following intravenous delivery. In vivo treatment resulted in a partial gain of CFTR function in epithelia as measured by in situ potential differences and Ussing chamber assays and correction of CFTR in both airway and GI tissues with no off-target effects above background. This is the first report of systemic gene editing for CF. Our data suggest that systemic delivery of PNA NPs designed to correct CF-causing mutations is a viable option to ameliorate the disease in multiple affected organs.

bioengineering↗

bioRxiv2021

Chromatin state transition underlies the temporal changes in gene expression during cardiomyocyte maturation

Congenital heart disease (CHD) is often rooted in gene expression anomalies that occur during heart development. As cells commit to a specific lineage, chromatin dynamics and developmental plasticity generally become more limited. However, it remains unclear how differentiated cardiomyocytes (CMs) undergo morphological and functional adaptations to the postnatal environment during their maturation. In this work, we sought to identify the regulatory mechanisms controlling postnatal cardiac gene networks. A time-series transcriptomic analysis of postnatal hearts revealed an integrated, time-ordered transcriptional network that regulates CM maturation. Remarkably, depletion of histone H2B ubiquitin ligase RNF20 after formation of the four-chamber heart disrupted these highly coordinated gene networks. Its ablation also caused early-onset cardiomyopathy, a phenotype reminiscent of CHD. Furthermore, we found that dynamic RNF20-mediated modulation of chromatin accessibility during CM maturation was necessary for the operative binding of cardiac transcription factors known to drive transcriptional gene networks. Together, our results reveal how epigenetic-mediated chromatin state transitions modulate time-ordered gene expression during CM maturation.

developmental biology↗

bioRxiv2021

Developing an Antiviral Peptides Predictor with Generative Adversarial Network Data Augmentation

MotivationNew antiviral drugs are urgently needed because of emerging viral pathogens increasing severity and drug resistance. Antiviral peptides (AVPs) have multiple antiviral properties and are appealing candidates for antiviral drug development. We developed a sequence-based binary classifier to identify whether an unknown short peptide has AVP activity. We collected AVP sequence data from six existing databases. We used a generative adversarial network to augment the number of AVPs in the positive training dataset and allow our deep convolutional neural network model to train on more data. ResultsOur classifier achieved outstanding performance on the testing dataset compared with other state-of-the-art classifiers. We deployed our trained classifier on a user-friendly web server. Availability and implementationAI4AVP is freely accessible at http://axp.iis.sinica.edu.tw/AI4AVP/ Contactcylin@iis.sinica.edu.tw Supplementary informationSupplementary data is also available.

microbiology↗