Biology subjects

Chen, Y.-Y.

Publications and source records attributed to Chen, Y.-Y..

34 records · Page 2Linked to original sources

bioRxiv2025

NCOR2 represses MHC class I molecule expression to drive metastatic progression of breast cancer

Metastatic progression depends upon the ability of disseminated tumor cells to evade immune surveillance. MHC molecule expression facilitates T cell recognition and activation to permit the eradication of metastatic tumor cells. We identified nuclear corepressor 2 (NCOR2) as a key epigenetic regulator of MHC class I molecule expression on breast tumor cells. Patients with triple negative breast cancers (TNBC) that expressed high levels of NCOR2 also exhibited reduced metastasis free survival and decreased MHC class I expression, and the metastatic lesions in patients with TNBC had high nuclear NCOR2 and reduced CD8 T cell levels and activity. Genetically and experimentally reducing NCOR2 expression in tumor cells permitted interferon gamma upregulation of MHC class I, and potentiated CD8 T cell activity and induction of apoptosis to repress metastatic progression of disseminated breast cancer cells. These studies provide evidence to support NCOR2 as a targetable epigenetic regulator of metastasis towards which therapies could be developed to reduce patient mortality.

cancer biology↗

bioRxiv2025

Single-nucleus multiomics of murine gonadal cells reveals transcriptional regulatory network underlying supporting lineage differentiation

Sex determination of mammalian gonads hinges upon sex-specific differentiation of gonadal supporting cells: Sertoli cells in the testis and granulosa cells in the ovary. To gain insights into how supporting cells acquire their identities, we performed joint single-nucleus transcriptomics and chromatin accessibility assays on murine gonadal cells across sex determination. By contrasting sex-specific gene expression and corresponding chromatin accessibility among progenitor and differentiated cells, we discovered that sex-specific chromatin regions in supporting cells are established shortly after sex determination, accompanied by the acquisition of active histone marks. The presence of potential transcription factor binding motifs in the open chromatin regions revealed regulatory networks underlying ovary-enriched factors LEF1 and MSX1, which promote granulosa fate by inducing granulosa-specific genes such as Foxl2 and Fst. Our results not only identify the gene regulatory framework underlying supporting cell sex differentiation, but also provide invaluable resources for the field. TeaserSex-specific changes in chromatin and gene expression underly the divergent developmental fates of the bipotential gonadal primordium.

developmental biology↗

bioRxiv2024

Warming treatments shift the temporal dynamics of diversity and composition of bacteria in wild blueberry soils.

Soil bacterial communities are a crucial biological indicator of soil health and crop performance; however, their response to climate change remains poorly understood. In Maine, wild blueberry farms are experiencing unprecedented temperature changes, which may exacerbate microbial responses and potentially harm the crop. To elucidate the response of bacterial communities to warming during the growing season, we employed passive and active open-top chambers to simulate climate warming scenarios in wild blueberry fields. Warming treatments elevated atmospheric temperatures by 1.2 and 3.3 {degrees}C (passive and active warming), respectively, but did not affect soil temperatures. Nevertheless, soils in the active warming treatment exhibited significantly lower water content than ambient conditions. Overall, soil bacterial diversity and richness (June, July, and August data combined) under the warming (passive and active) treatments and ambient controls did not demonstrate significant differences after two years of experimental warming. However, significantly higher bacterial evenness and diversity under warming treatments were observed in the early growing season (June). Our study also reveals pronounced seasonal shifts in the evenness and diversity of bacteria in wild blueberry soil, suggesting that the variation in bacterial community structure may be more influenced by seasonal changes in temperature and plant activity during the growing season than by warming treatments. The increased bacterial evenness and diversity under warming treatments in June may be attributed to advanced plant phenology, indicating a potential future shift in seasonal dynamics of bacterial activity under global warming.

microbiology↗

bioRxiv2024

MYC plus class IIa HDAC inhibition potentiates mitochondrial dysfunction in non-small cell lung cancer

MYC is frequently activated in cancer, leading to significant efforts to develop MYC inhibitors. While much progress has been made in targeting MYC, combination treatment strategies are needed to exploit this molecular vulnerability. To this end, we interrogated transcriptome data from cancer cell lines treated with MYC inhibitors and identified HDAC5 and HDAC9, both class IIa HDACs, as therapeutic targets to inhibit concurrently. Notably, these HDAC isoforms, which can be specifically targeted by small molecules, are known augmenters of several hallmarks of cancer. The combination of MYC and class IIa HDAC inhibition induces a significant reduction in viability for NSCLC cell lines with high MYC and mitochondrial pathway activation. Additionally, combination treatment induces a robust reduction of MYC with concomitant elevation of mitochondrial ROS, both of which have a causal relationship with therapeutic efficacy. Confirmation of in vivo efficacy was pursued in several animal model systems, with subsequent molecular correlate derivation confirming the importance of MYC depletion and mitochondrial dysfunction in driving drug efficacy. Ultimately, we define a therapeutic approach combining MYCi and class IIa HDACi to potentiate anti-tumor efficacy in NSCLC.

cancer biology↗

bioRxiv2024

Cellular heterogeneity in hypertrophic burn scars in response to carbon dioxide laser therapy

Fractional carbon dioxide (AFCO2) laser therapy is used for treating pathological scarring, but the clinical outcomes are variable and the mechanisms of scar reduction poorly understood. We investigated the mechanisms underpinning efficacy of AFCO2 laser therapy, performing single-cell RNA sequencing in skin biopsies from patients with hypertrophic scars after AFCO2 laser therapy. Patients with younger scars (Good Responder, GR, <6 years from healing) had better scar reduction than patients with older scars (Poor Responder, PR, >6 years from healing) by various measures of scarring. scRNAseq analysis revealed that genes enriched in GR were associated with extracellular matrix and structure organisation (COL14A1, POSTN, SPARC); whereas genes enriched in PR were related to enhanced immune responses (IL-12, MSTN, HLA-DQA). The groups had distinct intercellular communication networks and differentiation trajectories after AFCO2, with regenerative Mesenchymal fibroblasts associated with a good response and inflammatory Secretory Papillary and Inflammatory Fibroblasts with a poor response.

cell biology↗

bioRxiv2024

Pulsed sounds caused by internal oxygen transport during photosynthesis in the seagrass Halophila ovalis

Oxygen bubbles that leak from seagrass blades during photosynthesis have been hypothesized to cause cavitation sounds in aquatic plants. Here we investigate low-amplitude sounds with regular pulse rates produced during photosynthesis in seagrass beds of Halophila ovalis (Qitou Bay, Penghu islands and Cigu Lagoon, Taiwan). Sound pulses appear in the morning when illumination exceeds 10,000 Lux, peak at midday and decrease in midafternoon on a sunny day. Frequencies peak between 1 to 4 kHz, durations range between ca. 1.8 to 4.8 ms, and sound pressure level 1 cm from the bed is 80.3{+/-}2.0 dB re 1Pa (1-3 kHz band, 11:00 on a cloudy day). Sounds attenuate rapidly, disappearing beyond 15 cm. Blocking sunlight or administering herbicide stops ongoing sounds. Gas bubbles are not typically seen during sound production ruling out cavitation, and external force (finger pressing or scissor cutting) applied to the substrate of seagrass patch or leaves, petioles, or rhizomes generally increases pulse rate. We suggest sound emission is caused by internal oxygen transport through pores in diaphragms (a whistle mechanism) at the leaf base and nodes of the rhizome.

plant biology↗

bioRxiv2024

Single-nucleus multiomics reveals the gene-regulatory networks underlying sex determination of murine primordial germ cells

Accurate specification of female and male germ cells during embryonic development is critical for sexual reproduction. Primordial germ cells (PGCs) are the bipotential precursors of mature gametes that commit to an oogenic or spermatogenic fate in response to sex-determining cues from the fetal gonad. The critical processes required for PGCs to integrate and respond to signals from the somatic environment in gonads are not understood. In this study, we developed the first single-nucleus multiomics map of chromatin accessibility and gene expression during murine PGC development in both XX and XY embryos. Profiling of cell-type specific transcriptomes and regions of open chromatin from the same cell captured the molecular signatures and gene networks underlying PGC sex determination. Joint RNA and ATAC data for single PGCs resolved previously unreported PGC subpopulations and cataloged a multimodal reference atlas of differentiating PGC clusters. We discovered that regulatory element accessibility precedes gene expression during PGC development, suggesting that changes in chromatin accessibility may prime PGC lineage commitment prior to differentiation. Similarly, we found that sexual dimorphism in chromatin accessibility and gene expression increased temporally in PGCs. Combining single-nucleus sequencing data, we computationally mapped the cohort of transcription factors that regulate the expression of sexually dimorphic genes in PGCs. For example, the gene regulatory networks of XX PGCs are enriched for the transcription factors, TFAP2c, TCFL5, GATA2, MGA, NR6A1, TBX4, and ZFX. Sex-specific enrichment of the forkhead-box and POU6 families of transcription factors was also observed in XY PGCs. Finally, we determined the temporal expression patterns of WNT, BMP, and RA signaling during PGC sex determination, and our discovery analyses identified potentially new cell communication pathways between supporting cells and PGCs. Our results illustrate the diversity of factors involved in programming PGCs towards a sex-specific fate.

developmental biology↗

bioRxiv2023

Major axes of variation in tree demography across global forests

The future trajectory of global forests is closely intertwined with tree demography, and a major fundamental goal in ecology is to understand the key mechanisms governing spatial-temporal patterns in tree population dynamics. While historical research has made substantial progress in identifying the mechanisms individually, their relative importance among forests remains unclear mainly due to practical limitations. One approach is to group mechanisms according to their shared effects on the variability of tree vital rates and to quantify patterns therein. We developed a conceptual and statistical framework (variance partitioning of Bayesian multilevel models) that attributes the variability in tree growth, mortality, and recruitment to variation in species, space, and time, and their interactions, categories we refer to as organising principles (OPs). We applied the framework to data from 21 forest plots covering more than 2.9 million trees of approximately 6,500 species. We found that differences among species, the species OP, proved a major source of variability in tree vital rates, explaining 28-33% of demographic variance alone, and in interaction with space 14-17%, totalling 40-43%. The average variability among species declined with species richness across forests, indicating that diverse forests featured smaller interspecific differences in vital rates supporting the theory that the range of vital rates is similar across global forests. Decomposing the variance in vital rates into the proposed OPs showed that taxonomy is crucial to predicting and understanding tree demography on large forest plots. A focus on how variance is organized in forests can facilitate the construction of more targeted models with clearer expectations of which covariates might drive a vital rate. This study therefore highlights the most promising avenues for future research, both in terms of understanding the relative contributions of groups of mechanisms to forest demography and diversity, and for improving projections of forest ecosystems.

ecology↗

bioRxiv2022

Allee effects mediate the impact of land-use change on the thermal niche of social species

Land-use change not only affects habitat availability, it can also reduce population density and limit opportunities for interactions with conspecifics, further influencing species resilience to environmental challenges. For social species whose conspecific interactions are typically cooperative in nature, little is known about how land-use change influences demography and social behavior, and how this interaction impacts a species climatic niche. Here, we develop a spatially explicit, individual-based model to explore how land-use changes influence population size and niche width in social organisms through the Allee effect, the positive impact of higher population density on individual fitness. We then empirically test key model predictions by studying the distribution and cooperative behavior of burying beetles (Nicrophorus nepalensis) along elevational gradients in Taiwan. In support of our model predictions, we find that beetle densities are lower in areas of greater land-use change, making it harder for individuals in these hotter environments to form cooperative groups to compete against blowflies, their primary interspecific competitor. Consequently, the beetles lower distributional boundary is higher in areas with greater land-use change, indicating that the beetles thermal niche is reduced via Allee effects in human-altered landscapes. Ultimately, land-use change not only reduces habitat availability, it also shrinks the thermal niche of social species, making them more vulnerable to climate change.

ecology↗

bioRxiv2022

Negative Impact of Daily Screen Use on Inhibitory Control Network in Preadolescence: A Two Year Follow-Up Study

The COVID-19 pandemic has made an unprecedented shift in childrens daily lives. Children are increasingly spending time with screens to learn and connect with others. As the online environment rapidly substitutes in-person experience, understanding childrens neuropsychological trajectories associated with screen experiences is important. Previous findings suggest that excessive screen use can lead children to prefer more immediate rewards over delayed outcomes. We hypothesized that increased screen time delays a childs development of inhibitory control. By analyzing neuropsychological data from 8,324 children (9-11ys) from the ABCD Study, we found that children who had more screen time showed a higher reward orientation and a weaker inhibitory control system (i.e., fronto-striatal circuitry) in the brain. Importantly, we found that the interaction between screen exposure and reward sensitivity negatively influenced the development of the inhibitory control system in the brain over a two year period. These results indicate possible negative long-term impacts of increased daily screen time on childrens neuropsychological development. The results further demonstrated that screen time influences dorsal striatum connectivity, which suggests that the effect of daily screen use is a habitual seeking behavior. The study provides neural and behavioral evidence on the negative impact of daily screen use on developing children.

neuroscience↗

bioRxiv2021

A programmable probiotic encapsulation system enhances therapeutic delivery in vivo

Recent advances in therapeutic modulation of human microbiota have driven new efforts to engineer living microbial medicines using synthetic biology. However, a long-standing challenge for live bacterial therapies is balancing the high dose required to achieve robust efficacy with the potential for sepsis. Here, we developed a genetically encoded microbial encapsulation system with tunable and dynamic expression of surface capsular polysaccharides to enhance therapeutic delivery. Following a synthetic small RNA knockdown screen of the capsular biosynthesis pathway, we constructed synthetic gene circuits that regulate bacterial encapsulation based on sensing the levels of environmental inducer, bacterial density, and blood pH. The induced encapsulation system enabled tunable immunogenicity and survivability of the probiotic Escherichia coli, resulting in increased maximum tolerated dose and enhanced efficacy in murine cancer models. Furthermore, triggering in situ encapsulation was found to increase microbial translocation between mouse tumors, leading to efficacy in distal tumors. The programmable encapsulation system demonstrates a new approach to control microbial therapeutic profiles in vivo using synthetic biology.

synthetic biology↗

bioRxiv2020

Circulating microRNA-762 upregulates colorectal cancer might through Wnt-1/b-catenin signaling

BackgroundA number of microRNAs (miRNAs) have been demonstrated to be correlated with the diagnosis, progression and prognosis of colorectal cancer (CRC). However, the key miRNAs and the associated signaling pathways that regulate the growth and metastasis of CRC remain unclear. MethodsThe circulating miRNAs from BALB/c mice with CRC CT26 cell implantation were assayed by microarray. Then, mmu-miR-762 mimic and inhibitor were transfected to CT26 cells for analysis of cell viability, invasion, and epithelial-mesenchymal transition (EMT), cell cycle, and regulatory molecule expression. Human subjects were included for comparison the circulating has-miR-762 levels in CRC patients and control donors, as well as the patients with and without distant metastasis. ResultsThe miRNA levels in mice with CRC cell implantation indicated that plasma mmu-miR-762 was upregulated. Transfection of mmu-miR-762 mimic to CT26 cells increased cell viability, invasion, and EMT, whereas transfection of mmu-miR-762 inhibitor decreased the above abilities. Cells treated with high-concentration mmu-miR-762 inhibitor induced cell cycle arrest at G0/G1 phase. Western blot analysis showed that mmu-miR-762 mimic transfection upregulated the expression of Wnt-1 and {beta}-catenin. Further analysis was performed to demonstrate the correlation of has-miR-762 with CRC patients. The results showed that serum has-miR-762 levels in CRC patients were higher than in control donors. Among the CRC patients, patients with distant metastasis showed higher serum has-miR-762 levels than patients without distant metastasis. ConclusionsThe present study demonstrated that circulating miR-762 might be a biomarker with upregulation of CRC cell growth and invasion through the Wnt/{beta}-catenin signaling.

cell biology↗

bioRxiv2020

Prediction and discrimination of skeletal muscle function by bioelectrical impedance vector analysis using a standing impedance analyzer in healthy Taiwanese adults

BackgroundBioelectrical impedance vector analysis (BIVA) has been used for prediction of muscle performance. However, little is known about BIVA in Asian adults, and even less is known about using standing BIVA devices. Standing impedance analyzer allows quicker and more convenient way to gather data than conventional supine analyzer and is more suitable for clinical practice. This study aimed to investigate the relations between muscle function and BIVA parameters measured with a standing impedance analyzer in healthy Taiwanese adults. MethodsA total of 406 healthy subjects (age 34.5 {+/-} 17.3 years, body mass index 24.1 {+/-} 4.1 kg/m2) were recruited for BIVA and handgrip strength (HGS) measurements. Impedance parameters, including resistance (R) and reactance (Xc), were measured and normalized to body size by dividing by height (H). The resulting phase angle (PhA) was calculated. HGS in the dominant, left, and right hands were referred to as HGSDH, HGSLH, and HGSRH, respectively. All subjects were divided into 5 grades according to HGS. ResultsMuscle strength in the dominant, right, and left arms was correlated with variables in the order of sex, weight, age, height, Xc/H, and R/H (all, p < 0.001). Using all 6 variables, the determination coefficients were 0.792, 0.782, and 0.745, respectively, whereas the standard errors of estimates were 56.89, 58.01, and 56.67 N for HGSDH, HGSLH, and HGSRH, respectively. HGS was positively correlated with PhA, and negatively correlated with Xc/H and R/H. ConclusionsBIVA parameters measured with a standing impedance analyzer and anthropometric variables can predict and discriminate muscle function with good performance in healthy Asian adults.

physiology↗

bioRxiv2020

Ancestral duplicated DL/CRC orthologs display function on orchid reproductive organ innovation

The orchid flower is renowned for complexity of flower organ morphogenesis and has attracted great interest from scientists. The YABBY genes encode plant-specific transcription factors with important roles in vegetative and reproductive development in seed plants. DROOPING LEAF/CRABS CLAW (DL/CRC) orthologs are involved in reproductive organ development (especially carpels) of angiosperms. Orchid gynostemium (the fused organ of the androecium and gynoecium) and ovule development are unique developmental processes. Understanding the DL/CRC-like genes controlling the developmental program of the gynostemium and ovule could provide accessible information for reproductive organ molecular regulation in orchids. Two DL/CRC-like genes, named PeDL1 and PeDL2, were cloned from Phalaenopsis equestris. The orchid DL/CRC forms a monophyletic clade with two subclades including AshDL, PeDL1 and DcaDL1 in subclade I, and PeDL2 and DcaDL2 in subclade II. The temporal and spatial expression analysis indicated PeDL genes are specifically expressed in the gynostemium and at the early stages of ovule development. Both PeDLs could partially complement an Arabidopsis crc-1 mutant. Transient overexpression of PeDL1 in Phalaenopsis orchids caused abnormal development of ovule and stigmatic cavity of gynostemium. PeDL1, instead of PeDL2, could form a heterodimer with PeCIN8. Paralogue retention and subsequent divergence of the gene sequence of PeDL1 and PeDL2 in P. equestris might result in the differentiation of function and protein behaviors. These results reveal the important roles of PeDLs involved in orchid gynostemium and ovule development and provide new insights for further understanding the molecular mechanisms underlying orchid reproductive organ development.

developmental biology↗

bioRxiv2019

The cohesin loader NIPBL interacts with pre-ribosomal RNA and treacle to regulate ribosomal RNA synthesis

NIPBL is an essential loader of cohesin to mediate sister chromatid cohesion and chromatin loop organization. NIPBL mutations cause Cornelia de Lange Syndrome. How NIPBLs genomic localization is specified is not fully understood. We found that NIPBL localizes to the nucleolus in an RNA-dependent manner and binds directly to ribosomal RNA (rRNA). We identified two RNA binding domains in NIPBL in vitro, both of which are required for efficient rRNA binding in vivo. NIPBL binds to ribosomal DNA (rDNA) in an RNA-stimulated manner, recruits PAF1 and promotes pre-rRNA transcription. Stress that inhibits rRNA synthesis displaces NIPBL from the nucleolus and rDNA. Interestingly, treacle, mutated in Treacher Collins syndrome, tightly binds to and recruits NIPBL to the nucleolus, nucleolar organizer regions, and the stress-induced nucleolar cap. The results reveal that a subpopulation of NIPBL is recruited to the nucleolus through its interaction with RNA and treacle and regulates pre-rRNA transcription.

molecular biology↗

bioRxiv2017

The Effect Of Nipped-B-Like (Nipbl) Haploinsufficiency On Genome-Wide Cohesin Binding And Target Gene Expression: Modeling Cornelia de Lange Syndrome

Cornelia de Lange Syndrome (CdLS) is a multisystem developmental disorder frequently associated with heterozygous loss-of-function mutations of Nipped-B-like (NIPBL), the human homolog of Drosophila Nipped-B. NIPBL loads cohesin onto chromatin. Cohesin mediates sister chromatid cohesion important for mitosis, but is also increasingly recognized as a regulator of gene expression. In CdLS patient cells and animal models, the presence of multiple gene expression changes with little or no sister chromatid cohesion defect suggests that disruption of gene regulation underlies this disorder. However, the effect of NIPBL haploinsufficiency on cohesin binding, and how this relates to the clinical presentation of CdLS, has not been fully investigated. Nipbl haploinsufficiency causes CdLS-like phenotype in mice. We examined genome-wide cohesin binding and its relationship to gene expression using mouse embryonic fibroblasts (MEFs) from Nipbl +/- mice that recapitulate the CdLS phenotype. We found a global decrease in cohesin binding, including at CCCTC-binding factor (CTCF) binding sites and repeat regions. Cohesin-bound genes were found to be enriched for histone H3 lysine 4 trimethylation (H3K4me3) at their promoters; were disproportionately downregulated in Nipbl mutant MEFs; and displayed evidence of reduced promoter-enhancer interaction. The results suggest that gene activation is the primary cohesin function sensitive to Nipbl reduction. Over 50% of significantly dysregulated transcripts in mutant MEFs come from cohesin target genes, including genes involved in adipogenesis that have been implicated in contributing to the CdLS phenotype. Thus, decreased cohesin binding at the gene regions directly contributes to disease-specific expression changes. Taken together, our Nipbl haploinsufficiency model allows us to analyze the dosage effect of cohesin loading on CdLS development.

developmental biology↗