Biology subjects

Yang, Q.

Publications and source records attributed to Yang, Q..

At least 199 records · Page 11Linked to original sources

bioRxiv2024

Disconnection Between Microvascular Damage and Neurodegeneration in Early Diabetic Retinopathy

AimDiabetic retinopathy (DR) is a common complication of diabetes mellitus and can result in vision loss. Early clinically diagnosed signs of DR are linked to vascular damage, impacting on the neural retina typically at later stages. However, vascular changes and potential effects on neural cells before clinical diagnosis of DR are less understood. MethodsTo learn more about the earliest stages of DR we studied postmortem retina from diabetic donors who did not have clinical DR. Histological phenotyping and quantitative analysis were carried out on retina from 14 donors (3 controls, 10 diabetics, and 1 DR case) to examine capillary loss in the deeper vascular plexus (DVP) and the superficial vascular plexus (SVP) of the retinal vasculature and to study effects on the neural retina. ResultThe advanced DR case exhibited profound vascular and neural damage as expected, whereas none of the ten randomly selected diabetic donors had any DR signs that would have been diagnosed clinically. Within that group, two showed very minor capillary dropout in the SVP, whilst in the remaining diabetic cases the SVP was indistinguishable from the controls. In contrast, over half of the diabetic retinas showed capillary dropout in the DVP and increased capillary diameter. Furthermore, a pan retinal loss of inner nuclear layer cells was observed in those diabetics with capillary dropout compared to the controls (p<0.05), but there was no local spatial correlation between neural cell loss and capillary dropout. ConclusionsOur study has established a novel histological biomarker for diabetes related tissue damage at the earliest stages of DR in human postmortem retina, which appears to be common in people with diabetes before DR can be clinically diagnosed. Furthermore, the spatial mismatch between local capillary dropout and the diffuse neural loss in the INL suggests that at this very early stage of DR, microvascular loss may not causally be directly connected to neurodegeneration and that diabetes may affect the two readouts independently. RESEARCH IN CONTEXTWhat is already known about this subject? O_LIEarly DR is currently clinically defined by visible microvascular changes. C_LIO_LITests of retinal function in people with diabetes imply neuroretinal impairments in early DR. C_LIO_LIClinical imaging in people with diabetes suggests reduced perfusion in the deep retinal vasculature plexus. C_LI What is the key question? (one bullet point only; formatted as a question) O_LIHow does retinal microvascular damage relate to neuronal damage? C_LI What are the new findings? O_LIWe have developed a sensitive histological biomarker for microvascular damage in postmortem retinal tissue. C_LIO_LIEarly vascular changes in the deeper plexus occur in diabetes even in the absence of manifest DR. C_LIO_LINeurodegenerative changes are distributed throughout the retina in diabetes and do not spatially correlate with microvascular nonperfusion. C_LI How might this impact on clinical practice in the foreseeable future? O_LIDeeper plexus perfusion can be a useful early biomarker to assess DR. C_LI

pathology↗

bioRxiv2024

Postharvest partial dehydration of blueberries enhanced blueberry wine aroma via upregulating phenylalanine metabolism and terpene biosynthesis

Postharvest partial dehydration of blueberries can enhance blueberry wine aroma, while the underlying mechanisms remain unclear. In this study, the key odor-active volatiles in blueberry wines fermented from dehydrated blueberries (30% weight loss) were identified via aroma extract dilution analysis. Results showed that increased levels of phenylalanine-derived compounds such as phenylethanol, and terpenes such as linalool and geraniol, primarily led to the enhancement of sweet, floral and fruity aromas of blueberry wines. Postharvest partial dehydration increased the contents of these compounds, which could be linked to the upregulation of VcGOT2 and VcPAR involved in phenylalanine metabolism, and the upregulation of VcDXS, VcHDR and VcTPS involved in terpene biosynthesis. Notably, the upregulated VcTPS encoded a monoterpene synthase responsible for producing linalool. These findings provided insight into the impact of postharvest dehydration on phenylalanine and terpene metabolism in blueberries, offering a reference for improving blueberry wine aroma through postharvest partial dehydration techniques.

biochemistry↗

bioRxiv2024

YamOmics: A comprehensive data resource on yam multi-omics

Yams (Dioscorea spp.) are a highly important class of horticultural crops, serving as a staple food for millions of people in Africa and contributing significantly to food security. They are also widely cultivated in East Asia as medicinal herbs, bringing substantial economic incomes. Diverse omics data play a pivotal role in advancing yam research and breeding. However, these data are often scattered, lacking in systematic organization and analysis, which underscores the need for centralized and comprehensive data management. In view of this, we gathered extensive omics data and developed the Yam Omics Database (YamOmics; https://biotec.njau.edu.cn/yamdb). The database currently offers a vast and diverse range of omics data, covering genomic, transcriptomic and plastomic data from 41 distinct yam species, along with detailed records of genomic variants from [~]1000 germplasms, and gene expression profiles from [~]200 samples. Additionally, the database features thorough annotations, encompassing aspects like genome synteny, ortholog groups, signaling pathways, gene families and protein interactions. To support yam basic biology and breeding research, it is also equipped with a suite of user-friendly online tools, including PCR primer design, CRISPR design, expression analysis, enrichment analysis, and kinship analysis tools.

plant biology↗

bioRxiv2024

Mitotic waves in frog egg extracts: Transition from phase waves to trigger waves

Cyclin-dependent kinase 1 (Cdk1) activity rises and falls throughout the cell cycle, a cell-autonomous process known as mitotic oscillations. These oscillators can synchronize when spatially coupled, providing a crucial foundation for rapid synchronous divisions in large early embryos like Drosophila ([~] 0.5 mm) and Xenopus ([~] 1.2 mm). While diffusion alone cannot achieve such long-range coordination, recent studies have proposed two types of mitotic waves, phase and trigger waves, to explain the phenomena. How the waves establish over time for efficient spatial coordination remains unclear. Using Xenopus laevis egg extracts and a Cdk1 FRET sensor, we observe a transition from phase waves to a trigger wave regime in an initially homogeneous cytosol. Adding nuclei accelerates such transition. Moreover, the system transitions almost immediately to this regime when externally driven by metaphase-arrested extracts from the boundary. Employing computational modeling, we pinpoint how wave nature, including speed-period relation, depends on transient dynamics and oscillator properties, suggesting that phase waves appear transiently due to the time required for trigger waves to entrain the system and that spatial heterogeneity promotes entrainment. Therefore, we show that both waves belong to a single biological process capable of coordinating the cell cycle over long distances.

biophysics↗

bioRxiv2024

Modeling and Correction of Protein Conformational Disease in iPSC-derived Neurons through Personalized Base Editing

AbstractAltered protein conformation can cause incurable neurodegenerative disorders. Mutations in SERPINI1, the gene encoding neuroserpin, can alter protein conformation resulting in cytotoxic aggregation leading to neuronal death. Familial encephalopathy with neuroserpin inclusion bodies (FENIB) is a rare autosomal dominant progressive myoclonic epilepsy that progresses to dementia and premature death. We developed HEK293T and induced pluripotent stem cell (iPSC) models of FENIB, harboring a patient-specific pathogenic SERPINI1 variant or stably overexpressing mutant neuroserpin fused to GFP (MUT NS-GFP). Here, we utilized a personalized adenine base editor (ABE)-mediated approach to correct the pathogenic variant efficiently and precisely to restore neuronal dendritic morphology. ABE-treated MUT NS-GFP cells demonstrated reduced inclusion size and number. Using an inducible MUT NS-GFP neuron system, we identified early prevention of toxic protein expression allowed aggregate clearance, while late prevention halted further aggregation. To address several challenges for clinical applications of gene correction, we developed a neuron-specific engineered virus-like particle to optimize neuronal ABE delivery, resulting in higher correction efficiency. Our findings provide a targeted strategy which may treat FENIB and potentially other neurodegenerative diseases due to altered protein conformation such as Alzheimers and Huntingtons diseases.

molecular biology↗

bioRxiv2023

Mutation of OsCDS5 confers broad-spectrum disease resistance in rice

Phospholipids are important components of biological membranes, participating in various biological processes, including plant development and responses to biotic and abiotic stresses. A previous study showed that mutation of the rice OsCDS5 (CDP-DAG Synthase) gene alters lipid metabolism, causing enhanced abiotic stress responses, yellowing of leaves at the seedling stage and delayed plant development. Here, we observed that the Oscds5 mutant shows enhanced resistance to rice blast, bacterial blight and bacterial leaf streak. Mutation of OsCDS5 promotes production of reactive oxygen species (ROS) and increases the expression level of multiple defense-related genes. Transcriptomic analyses indicate that genes involved in responses to stress, biotic/abiotic stimuli and metabolic processes are highly upregulated and enriched in mutant Oscds5. Metabolomic analyses show that differential metabolites are enriched in the lipid metabolic and tryptophan metabolic pathways. The decreased level of phosphatidylinositol (PI) and increased level of serotonin likely contribute to enhanced disease resistance of the Oscds5 mutant. Taken together, mutation of OsCDS5 enhances abiotic and biotic stress responses, and OsCDS5 may be a promising target in genetic engineering to enhance the resilience of rice to abiotic and biotic stresses simultaneously.

plant biology↗

bioRxiv2023

Social cognitive regions of human association cortex are selectively connected to the amygdala

Reasoning about someones thoughts and intentions - i.e., forming a theory of mind - is an important aspect of social cognition that relies on association areas of the brain that have expanded disproportionately in the human lineage. We recently showed that these association zones comprise parallel distributed networks that, despite occupying adjacent and interdigitated regions, serve dissociable functions. One network is selectively recruited by theory of mind processes. What circuit properties differentiate these parallel networks? Here, we show that social cognitive association areas are intrinsically and selectively connected to regions of the anterior medial temporal lobe that are implicated in emotional learning and social behaviors, including the amygdala at or near the basolateral complex and medial nucleus. The results suggest that social cognitive functions emerge through coordinated activity between amygdala circuits and a distributed association network, and indicate the medial nucleus may play an important role in social cognition in humans.

neuroscience↗

bioRxiv2023

'Drifting' Buchnera genomes track the microevolutionary trajectories of their aphid hosts

Evolution of Buchnera-aphid host symbioses is often studied among species at macroevolutionary scales. Investigations within species offer a different perspective about how eco-evolutionary processes shape patterns of genetic variation at microevolutionary scales. Our study leverages new and publicly available whole-genome sequencing data to study Buchnera-aphid host evolution in Myzus persicae, the peach potato aphid, a globally invasive and polyphagous pest. Across 43 different asexual, clonally reproducing isofemale strains, we examined patterns of genomic covariation between Buchnera and their aphid host and considered the distribution of mutations in protein-coding regions of the Buchnera genome. We found Buchnera polymorphisms within aphid strains, suggesting the presence of genetically different Buchnera strains within the same clonal lineage. Genetic distance between pairs of Buchnera samples was positively correlated to genetic distance between their aphid hosts, indicating shared evolutionary histories. However, there was no segregation in the genetic variation of both M. persicae and Buchnera with plant host (Brassicaceae and non-tobacco Solanaceae) and no associations between genetic and geographic distance at global or regional spatial scales. Abundance patterns of non-synonymous mutations were similar to synonymous mutations in the Buchnera genome, and both mutation classes had similar site frequency spectra. We hypothesize that a predominance of neutral processes results in the Buchnera of M. persicae to simply drift with the evolutionary trajectory of their aphid hosts. Our study presents a unique microevolutionary characterisation of Buchnera-aphid host genomic covariation across multiple aphid clones. This provides a new perspective on the eco-evolutionary processes generating and maintaining polymorphisms in a major pest aphid species and its obligate primary endosymbiont.

evolutionary biology↗

bioRxiv2023

Paternal genomic resources from the YanHuang cohort suggested a Weakly-Differentiated Multi-source Admixture model for the formation of Hans founding ancestral lineages

The large-scale human genome revolution and rapidly advanced statistical innovation have updated our understanding of the fine-scale and complex genetic structure, the entire landscape of genetic diversity and the evolutionary trajectories of spatiotemporally different ancients and ethnolinguistically diverse modern populations. Recent ancient DNA research provided a detailed and complex admixture picture of ancient Europeans but limited insights into East Asians as the few available genomes. Y-chromosome variations in the male-specific regions, served as molecular archaeological tool, have unique evolutionary features that can be utilized to reconstruct the origin and subsequent interaction of ancient East Asian paternal lineages. We launched the YanHuang cohort using our designed highest-resolution capture sequencing panel to explore the detailed evolutionary trajectory of the Han Chinese, one of the largest ethnic groups in the world. We reported one of the largest uniparental genomic resources and observed multiple founding paternal lineages dominant in ancient western Eurasian, Siberian and East Asian participating in the formation of the gene pool of the Han Chinese. We identified fine-scale paternal genetic structure correlated with different patterns of ancient population interaction and geographical mountain barriers (Qinling-Huaihe line and Nanling Mountains), suggesting isolation-enhanced and admixture-introduced genetic differentiation enhanced the complexity of the Han Chinese genomic diversity. We observed a strong direct correlation between the frequency of multiple founding lineages of the Han Chinese and the proportion of subsistence-related ancestry sources related to western pastoralists, Holocene Mongolian Plateau people and ancient East Asians, reflecting the ancient migration events contributed to our identified patterns of Chinese paternal genomic diversity. We finally provided one novel and the most plausible admixture-by-admixture model, the Weakly-Differentiated Multi-Source Admixture model, as the major genetic mechanism to illuminate our observed pattern of complex interactions of multiple ancestral sources and landscape of the Han Chinese paternal genetic diversity. Generally, we presented one large-scale uniparental genomic resource from the YanHuang cohort, portrayed one novel admixture formation model and presented the entire genomic landscape with multiple ancestral sources related to ancient herders, hunter-gatherers and farmers who participated in the ancestral formation of the Han Chinese.

evolutionary biology↗

bioRxiv2023

Infection pressure in apes has driven selection for CD4 alleles that resist lentivirus (HIV/SIV) infection

Simian immunodeficiency viruses (SIVs) comprise a large group of primate lentiviruses that endemically infect African monkeys. HIV-1 spilled over to humans from this viral reservoir, but the spillover did not occur directly from monkeys to humans. Instead, a key event was the introduction of SIVs into great apes, which then set the stage for infection of humans. Here, we investigate the role of the lentiviral entry receptor, CD4, in this key and fateful event in the history of SIV/HIV emergence. First, we reconstructed and tested ancient forms of CD4 at two important nodes in ape speciation, both prior to the infection of chimpanzees and gorillas with these viruses. These ancestral CD4s fully supported entry of diverse SIV isolates related to the viruses that made this initial jump to apes. In stark contrast, modern chimpanzee and gorilla CD4 orthologs are more resistant to these viruses. To investigate how this resistance in CD4 was gained, we acquired CD4 gene sequences from 32 gorilla individuals of two species, and identified alleles that encode 8 unique CD4 protein variants. Functional testing of these identified variant-specific differences in susceptibility to virus entry. By engineering single point mutations from resistant gorilla CD4 variants into the permissive human CD4 receptor, we demonstrate that acquired substitutions in gorilla CD4 did convey resistance to virus entry. We provide a population genetic analysis to support the theory that selection is acting in favor of more and more resistant CD4 alleles in ape species harboring SIV endemically (gorillas and chimpanzees), but not in other ape species that lack SIV infections (bonobos and orangutans). Taken together, our results show that SIV has placed intense selective pressure on ape CD4, acting to propagate SIV-resistant alleles in chimpanzee and gorilla populations.

microbiology↗

bioRxiv2023

High clonal diversity and spatial genetic admixture in early prostate cancer and surrounding normal tissue

Somatic copy number alterations (SCNAs) are pervasive in advanced human cancers, but their prevalence and spatial distribution in early-stage, localized tumors and their surrounding normal tissues are poorly characterized. Here, we performed multi-region, single-cell DNA sequencing to characterize the SCNA landscape across multiple tumor-rich and normal tissue regions ([~]125 mm3 tissue cubes) obtained from prostatectomy performed in two patients with localized prostate cancer. We identified two distinct populations of cells with abnormal karyotypes, one marked by sparse deletions or amplifications ( pseudo-diploid cells) and the second characterized by genome-wide copy number changes reminiscent of monster cells previously described in colorectal cancer. Pseudo-diploid cells formed numerous small-sized subclones ranging from highly spatially localized to broadly spread subclones mainly featuring (sub-)chromosomal arm deletions. In contrast, monster cells harbored whole-chromosome gains and losses and were mostly singular events detected throughout the prostate, including normal tissue regions. Targeted deep sequencing of cancer-associated genes revealed a more confined pattern of mutations overlapping with tumor-rich regions, although we also detected mutations in regions deemed normal based on morphological assessment and bulk RNA-seq. Highly localized pseudo-diploid subclones were confined within tumor-rich regions and typically carried deletions involving chromosome (chr) 6 and 13, resulting in simultaneous loss of multiple tumor-suppressor genes, including FOXO1 and FOXO3 encoding two transcription factors belonging to the Forkhead family previously implicated in prostate carcinogenesis. Tumor-rich regions also contained mutations in genes frequently mutated in prostate cancer, including FOXA1, LRP1B, SPOP, and SPTA1. Our study reveals that SCNAs are widespread in both normal and tumor regions across the prostate gland of patients with localized prostate cancer and suggests that a subset of pseudo-diploid cells harboring chromosomal deletions that result in the loss of specific tumor-suppressor genes drive tumorigenesis in the aging prostate.

cancer biology↗

bioRxiv2023

Analysis of the comparative strengths of intramural and extramural grant funding mechanisms

Funding agencies use a variety of mechanisms to fund research. The National Institutes of Health in the United States, for example, employs scientists to perform research at its own laboratories (intramural research), and it also awards grants to pay for research at external institutions such as universities (extramural research). Here, using data from 1594 intramural grants and 97054 extramural grants funded between 2009 and 2019, we compare the scholarly outputs from these two funding mechanisms in terms of number of publications, relative citation ratio and clinical metrics. We find that extramural awards are more cost-effective for producing outputs commonly used for academic evaluation, such as publications and citations (per dollar), while intramural awards are more cost-effective for generating research that influences future clinical work, more closely in line with the agencys health goals. These findings provide evidence that institutional incentives associated with different funding mechanisms drive their comparative strengths.

scientific communication and education↗

bioRxiv2023

A human pluripotent stem cell-based somitogenesis model using microfluidics

Emerging human pluripotent stem cell (hPSC)-based embryo models are useful for studying human embryogenesis. Particularly, there are hPSC-based somitogenesis models using free-floating culture that recapitulate somite formation. Somitogenesis in vivo involves intricately orchestrated bio-chemical and -mechanical events. However, none of the current somitogenesis models controls biochemical gradients or biomechanical signals in the culture, limiting their applicability to untangle complex biochemical-biomechanical interactions that drive somitogenesis. Here we report a new human somitogenesis model by confining hPSC-derived presomitic mesoderm (PSM) tissues in microfabricated trenches. Exogenous microfluidic morphogen gradients imposed on PSM cause axial patterning and trigger spontaneous rostral-to-caudal somite formation. A mechanical theory is developed to explain the size dependency between somites and PSM. The microfluidic somitogenesis model is further exploited to reveal regulatory roles of cellular and tissue biomechanics in somite formation. This study presents a useful microengineered, hPSC-based model for understanding the bio-chemical and -mechanical events that guide somite formation.

bioengineering↗

bioRxiv2023

Acute toxicity effects of pesticides on predatory snout mites (family Bdellidae)

Predatory mites biologically control a range of arthropod crop pests and are often central to agricultural IPM strategies globally. Conflict between chemical and biological pest control has prompted increasing interest in selective pesticides with fewer off-target impacts on beneficial invertebrates, including predatory mites. However, the range of predatory mite species included in standardised pesticide toxicity assessments does not match the diversity of naturally-occurring species contributing to biocontrol, with most testing carried out on species from the family Phytoseiidae. Here, we aim to bridge this knowledge gap by investigating the impacts of 22 agricultural pesticides on the predatory snout mite Odontoscirus lapidaria (Kramer) (family Bdellidae). Using internationally standardised testing methodologies, we identified several active ingredients with minimal impact on O. lapidaria mortality, including Bacillus thuringiensis, nuclear polyhedrosis virus, flonicamid, afidopyropen, chlorantraniliprole and cyantraniliprole, which may therefore be good candidates for IPM strategies utilising both chemical and biological control. Importantly, we reveal differences between Bdellidae and Phytoseiidae in responses to a number of chemicals, including the miticides diafenthiuron and abamectin, highlighting the risk of making generalisations around acute toxicity based on tests with one beneficial mite family. We also explored the impacts of several pesticides on a second Bdellidae species and found differences in the response to chlorpyrifos compared with O. lapidaria, further highlighting the taxon-specific nature of non-target toxicity effects.

pharmacology and toxicology↗

bioRxiv2023

Oligodendroglial precursors orchestrate immune network instigating early demyelination in experimental autoimmune encephalomyelitis

The immunomodulatory cellular network that triggers early inflammation and demyelination, the key steps in multiple sclerosis (MS) pathogenesis remains poorly characterized. Here, we demonstrate that overactivation of Wnt pathway promotes pathological transformation of oligodendrocyte precursor cells (OPCs) to replicate pathological OPCs in human MS. In mouse experimental autoimmune encephalomyelitis (EAE), pathological OPCs attract CD4+ T-helper 1 (Th1) cells into the spinal cord and brain through CC-chemokine ligand 4 (CCL4), whilst OPCs cooperate with Th1 cells inducing transformation of cytotoxic macrophages that execute early demyelination. Simultaneously, Th1 cells and cytotoxic macrophages upregulate Wnt signaling and CCL4 expression in OPCs, thus exerting positive feedback onto the OPC-immune cascade and establishing a vicious cycle propagating EAE pathogenesis. Breaking this cascade by targeting CCL4 reduces immune cell infiltration, alleviates demyelination, and attenuates EAE severity. Our findings demonstrate a closely coordinated network of OPCs and immune cells therefore providing an alternative insight into MS pathophysiology.

neuroscience↗

bioRxiv2023

A wave of minor de novo DNA methylation initiates in mouse 8-cell embryos and co-regulates imprinted X- chromosome inactivation

DNA methylation is extensively reprogrammed during early stage of mammalian development and is essential for normal embryogenesis. It is well established that mouse embryos acquire genome-wide DNA methylation during implantation, referred to as de novo DNA methylation, from globally hypomethylated blastocysts. However, the fact that the main de novo DNA methyltransferase 3B (DNMT3B) is initially expressed as early as the 8-cell stage, contradicts the current knowledge about timing of initiation of de novo DNA methylation. Here, we reported that a previously overlooked minor wave of de novo DNA methylation initially occurs during the transition from the 8-cell to blastocyst stage, before the well-known large-scale de novo DNA methylation during implantation. Functional analyses indicated that minor de novo DNA methylation regulates proliferation, lineage differentiation and metabolic homeostasis of preimplantation embryos, and is critical for embryonic developmental potential and pregnancy outcomes. Furthermore, bioinformatic and functional analyses indicated that minor de novo DNA methylation preferentially occurs on the X chromosome and co-regulates imprinted X-chromosome inactivation via the interaction between DNMT3B and polycomb repressive complexes 2 core components during blastocyst formation. Thus, our study updates the current knowledge of embryonic de novo DNA methylation, thereby providing a novel insight of early embryonic epigenetic reprogramming. Summary statementA minor wave of de novo DNA methylation has been initiated prior to blastocyst formation, but not during the implantation period, and co-regulates imprinted X-chromosome inactivation.

developmental biology↗

bioRxiv2023

ONECUT2 Activates Diverse Resistance Drivers of Androgen Receptor-Independent Heterogeneity in Prostate Cancer

Significance StatementONECUT2 (OC2) is a master transcription factor that alters lineage identity by activating gene networks associated with both neuroendocrine prostate cancer and prostate adenocarcinoma. A small molecule inhibitor of OC2 represses the lineage plasticity program activated by enzalutamide, suggesting OC2 inhibition as a novel therapeutic strategy to prevent emergence of treatment-resistant variants. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=135 SRC="FIGDIR/small/560025v2_ufig1.gif" ALT="Figure 1"> View larger version (41K): org.highwire.dtl.DTLVardef@13278a4org.highwire.dtl.DTLVardef@8e82aeorg.highwire.dtl.DTLVardef@25a115org.highwire.dtl.DTLVardef@728eb4_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphic AbstractC_FLOATNO C_FIG Androgen receptor-(AR-) indifference is a mechanism of resistance to hormonal therapy in prostate cancer (PC). Here we demonstrate that the HOX/CUT transcription factor ONECUT2 (OC2) activates resistance through multiple drivers associated with adenocarcinoma, stem-like and neuroendocrine (NE) variants. Direct OC2 targets include the glucocorticoid receptor and the NE splicing factor SRRM4, among others. OC2 regulates gene expression by promoter binding, enhancement of chromatin accessibility, and formation of novel super-enhancers. OC2 also activates glucuronidation genes that irreversibly disable androgen, thereby evoking phenotypic heterogeneity indirectly by hormone depletion. Pharmacologic inhibition of OC2 suppresses lineage plasticity reprogramming induced by the AR signaling inhibitor enzalutamide. These results demonstrate that OC2 activation promotes a range of drug resistance mechanisms associated with treatment-emergent lineage variation in PC. Our findings support enhanced efforts to therapeutically target this protein as a means of suppressing treatment-resistant disease.

cancer biology↗

bioRxiv2023

GeneCompass: Deciphering Universal Gene Regulatory Mechanisms with Knowledge-Informed Cross-Species Foundation Model

Deciphering the universal gene regulatory mechanisms in diverse organisms holds great potential to advance our knowledge of fundamental life process and facilitate research on clinical applications. However, the traditional research paradigm primarily focuses on individual model organisms, resulting in limited collection and integration of complex features on various cell types across species. Recent breakthroughs in single-cell sequencing and advancements in deep learning techniques present an unprecedented opportunity to tackle this challenge. In this study, we developed GeneCompass, the first knowledge-informed, cross-species foundation model pre-trained on an extensive dataset of over 120 million single-cell transcriptomes from human and mouse. During pre-training, GeneCompass effectively integrates four types of biological prior knowledge to enhance the understanding of gene regulatory mechanisms in a self-supervised manner. Fine-tuning towards multiple downstream tasks, GeneCompass outperforms competing state-of-the-art models in multiple tasks on single species and unlocks new realms of cross-species biological investigation. Overall, GeneCompass marks a milestone in advancing knowledge of universal gene regulatory mechanisms and accelerating the discovery of key cell fate regulators and candidate targets for drug development.

bioinformatics↗