Biology subjects

Lu, C.

Publications and source records attributed to Lu, C..

At least 55 records · Page 3Linked to original sources

bioRxiv2025

The Neurocognitive Mechanisms Underlying Narrative Schematic and Paraphrastic Transmission

Narrative transmission serves multiple crucial functions, such as cultural preservation, knowledge accumulation, and consensus building, in human society. However, our understanding of its neurocognitive mechanisms remains limited. In this study, we combined a social transmission chain design with fMRI to investigate the dynamic changes of different narrative components occurring throughout transmission chains and to uncover the factors driving fidelity and distortion. A total of 58 participants were scanned as they listened to and subsequently recalled a story within a social transmission chain. We distinguished two types of transmission modes: schematic transmission, which prioritizes preserving the structural framework of the information, and paraphrastic transmission, which entails rephrasing the content while conveying its meaning. Behavioral results revealed a pattern in which paraphrastic transmission led to distortion and divergence, whereas schematic transmission remained more stable and convergent. Neural findings indicated that the transmission of story structure and content involved subsystems of the Default Mode Network (DMN) and specific subregions of the Hippocampus (HPC). While neural reinstatement between narrative listening and speaking failed to predict across-generation fidelity of content and structure, functional connectivity pattern similarity analysis showed that the DMN and HPC work as an episodic memory system supporting transmission performance. These findings highlight that narrative transmission is supported by distinct neurocognitive representations within episodic memory subsystems, which work collaboratively to sustain the transmission of narratives.

neuroscience↗

bioRxiv2025

A cell-type specific surveillance complex represses cryptic promoters during differentiation in an adult stem cell lineage

Regulators of chromatin accessibility play key roles in cell fate transitions, triggering onset of novel transcription programs as cells differentiate. In the Drosophila male germ line stem cell lineage, tMAC, a master regulator of spermatocyte differentiation that binds thousands of loci, is required for local opening of chromatin, allowing activation of spermatocyte-specific promoters. Here we show that a cell-type specific surveillance system involving the multiple zinc finger protein Kmg and the pipsqueak domain protein Dany dampens transcriptional output from weak tMAC dependent promoters and blocks tMAC binding at thousands of additional cryptic promoters, thus preventing massive expression of aberrant protein-coding transcripts. ChIP-seq showed Kmg enriched at the tMAC-bound promoters it repressed, consistent with direct action. In contrast, Kmg and Dany did not repress highly expressed tMAC dependent genes, where they colocalized with their binding partner, the chromatin modeler Mi-2 (NuRD), along the transcribed regions rather than at the promoter. Mi-2 has been shown to preferentially bind RNA over chromatin (Ullah et al. 2022). We propose that at highly expressed genes binding of Mi-2 to the abundant nascent RNA pulls the Kmg/Dany complex away from promoters, providing a mechanism to effectively repress ectopic promoters while protecting robust transcription.

developmental biology↗

bioRxiv2025

Multi-omic Characterization of HIV Effects at Single Cell Level across Human Brain Regions

HIV infection exerts profound and long-lasting neurodegenerative effects on the central nervous system (CNS) that can persist despite antiretroviral therapy (ART). Here, we used single-nucleus multiome sequencing to map the transcriptomic and epigenetic landscapes of postmortem human brains from 13 healthy individuals and 20 individuals with HIV who have a history of treatment with ART. Our study spanned three distinct regions--the prefrontal cortex, insular cortex, and ventral striatum--enabling a comprehensive exploration of region-specific and cross-regional perturbations. We found widespread and persistent HIV-associated transcriptional and epigenetic alterations across multiple cell types. Detailed analyses of microglia revealed state changes marked by immune activation and metabolic dysregulation, while integrative multiomic profiling of astrocytes identified multiple subpopulations, including a reactive subpopulation unique to HIV-infected brains. These findings suggest that cells from people with HIV exhibit molecular shifts that may underlie ongoing neuroinflammation and CNS dysfunction. Furthermore, cell-cell communication analyses uncovered dysregulated and pro-inflammatory interactions among glial populations, underscoring the multifaceted and enduring impact of HIV on the brain milieu. Collectively, our comprehensive atlas of HIV-associated brain changes reveals distinct glial cell states with signatures of pro-inflammatory signaling and metabolic dysregulation, providing a framework for developing targeted therapies for HIV-associated neurological dysfunction.

bioinformatics↗

bioRxiv2024

Fluid replacement and acute systemic inflammatory response syndrome during eight-hour extreme heat exposure in young men

Prolonged exposure to extreme heat poses significant risks, including systemic inflammatory response syndrome (SIRS), organ damage and hormonal imbalance. While fluid replacement is commonly recommended to mitigate these effects, its efficacy under uncompensable heat stress remains unclear. This study investigated the impacts of fluid replacement on thermoregulation, systemic inflammation, organ stress, cortisol levels and plasma electrolyte balance during eight-hour of extreme heat exposure in healthy young men. Twelve participants (age: 24.7{+/-}1.6 years; body surface area: 1.9{+/-}0.1 m{superscript 2}) underwent two randomized trials (dehydration: 125 mL/hour; euhydration: 375 mL/hour) in a heat chamber (40 {degrees}C, 55% RH). Biomarkers of inflammation (e.g., IL-6, IL-1{beta}), oxidative stress (e.g., MDA, SOD), organ function (ALT, BUN), cortisol, and electrolytes (sodium, potassium, chloride) were measured before and after exposure. Core temperature (Tcore) was continuously monitored. Results showed that fluid replacement significantly reduced Tcore at the end of the exposure (38.0{+/-}0.12 {degrees}C vs. 38.2{+/-}0.10 {degrees}C, p=0.046). However, it exacerbated systemic inflammation (IL-6: euhydration 19.8{+/-}4.3 pg/mL vs. dehydration 12.5{+/-}2.8 pg/mL, p<0.01) and liver stress (ALT: euhydration 45.3{+/-}6.7 U/L vs. dehydration 34.1{+/-}5.5 U/L, p=0.03). Cortisol levels decreased significantly in the euhydration group (p=0.041), potentially indicating attenuated stress resilience. Electrolyte imbalances (reduced sodium and potassium concentrations) were observed in the euhydration condition. Taken together, while fluid replacement reduced Tcore, it did not mitigate SIRS and instead exacerbated systemic inflammation, liver stress, and electrolyte imbalances, potentially through hypotonic osmotic stress. These findings underscore the need for personalized hydration strategies that balance fluid and electrolyte intake during extreme heat exposure to minimize health risks. Key pointsO_LIThis study investigated the effects of fluid replacement on acute inflammatory responses, thermoregulation, and organ stress markers in healthy young males exposed to eight hours of uncompensable heat stress. C_LIO_LIFluid replacement did not mitigate acute systemic inflammatory response syndrome (SIRS) but exacerbated inflammatory and organ stress markers despite reducing core temperature. C_LIO_LICore temperatures remained significantly lower in the euhydration group, but systemic and hepatic inflammatory markers worsened, highlighting the complexity of hydration strategies under extreme heat. C_LIO_LIWe emphasize the need for individualized hydration strategies incorporating electrolyte balance and sweat rate monitoring to minimize SIRS risk. C_LIO_LIWe provide actionable insights into heat stress physiology, with implications for occupational health guidelines, public health policies, and climate change adaptation. C_LI

physiology↗

bioRxiv2024

Paired CRISPR screens to map gene regulation in cis and trans

Recent massively-parallel approaches to decipher gene regulatory circuits have focused on the discovery of either cis-regulatory elements (CREs) or trans-acting factors. Here, we develop a scalable approach that pairs cis- and trans-regulatory CRISPR screens to systematically dissect how the key immune checkpoint PD-L1 is regulated. In human pancreatic ductal adenocarcinoma (PDAC) cells, we tile the PD-L1 locus using [~]25,000 CRISPR perturbations in constitutive and IFN{gamma}-stimulated conditions. We discover 67 enhancer- or repressor-like CREs and show that distal CREs tend to contact the promoter of PD-L1 and related genes. Next, we measure how loss of all [~]2,000 transcription factors (TFs) in the human genome impacts PD-L1 expression and, using this, we link specific TFs to individual CREs and reveal novel PD-L1 regulatory circuits. For one of these regulatory circuits, we confirm the binding of predicted trans-factors (SRF and BPTF) using CUT&RUN and show that loss of either the CRE or TFs potentiates the anti-cancer activity of primary T cells engineered with a chimeric antigen receptor. Finally, we show that expression of these TFs correlates with PD-L1 expression in vivo in primary PDAC tumors and that somatic mutations in TFs can alter response and overall survival in immune checkpoint blockade-treated patients. Taken together, our approach establishes a generalizable toolkit for decoding the regulatory landscape of any gene or locus in the human genome, yielding insights into gene regulation and clinical impact.

genomics↗

bioRxiv2024

R-Spondin Mimetic, SZN-043, Induced Proliferation and Wnt Activity, Two Features Deficient in Human Alcohol-Associated Liver Disease

Liver regeneration is impaired in patients suffering from alcohol-associated liver (ALD) diseases. Wnt ligands and their FZD receptors are dysregulated in diseased livers. R-spondin and their receptors are known to regulate Wnt activity via the stabilization of FZD receptors. Here, we investigated the components of the Wnt and R-Spondin-signaling pathways and their activity in patients with ALD. We found that while hepatocytes retained high levels of differentiation markers such as ASGR1 and ASGR2, the expression of two R-spondin co-receptors, LGR4 and LGR5, and of Wnt target genes, CYP1A2 and others, were strongly reduced. SZN-043, a hepatocyte-targeted R-Spondin mimetic, is a new investigational drug that stimulates the physiological Wnt repair pathway and proliferation of hepatocytes. Here, we show that SZN-043 induced hepatocyte proliferation in all models tested, including humanized mouse livers, a chronic-binge alcohol-induced liver injury, and a CCl4-induced fibrosis mouse model. Altogether, SZN-043 could be beneficial for the treatment of ALD.

pathology↗

bioRxiv2024

gen3DNet: An R Package for Generating 3D Network Models

MotivationNetworks are ubiquitous to organize and represent data in the real world such as the biomedical networks, social networks, etc. Due to the attractive property of networks which can explicitly capture the rich relationships among data samples, there is an increasing demand to transform linkage-free data to graph-structure data for efficient downstream analyses. Existing works typically focus on representing a single data object like gene expression profile in a homogeneous 2D network, which fail to deal with situations where two different data objects are involved to create a 3D heterogeneous network. ResultsIn this paper, we introduce an R package, gen3DNet (a generic version of the iPhDNet), for generating 3D network models from two correlated objects with shared common factors. Specifically, gen3DNet builds the relationships between samples and shared factors using the non-negative matrix factorization, where three clustering techniques are evaluated to determine the number of functional modules. In addition, it builds the relationships between samples from the two distinct data objects based on a partial least squares regression model. Usage of the package is illustrated through a real-world application. GitHub URL Source code is available at https://github.com/mollahlab/gen3DNet

bioinformatics↗

bioRxiv2024

An integrative proteotranscriptomics approach reveals new ADAM9 substrates and downstream pathways

The disintegrin metalloprotease ADAM9 is a cell-surface protease that can shed the ectodomain of membrane protein substrates. Dysregulated ADAM9 activity has been implicated in several diseases such as solid tumors, autoimmunity, inflammatory diseases, and COVID-19. Despite its importance, the substrates and targets of ADAM9 in normal and pathological processes are poorly understood. Here, we developed an integrative proteotranscriptomics approach to systematically identify the transcriptional and post-transcriptional targets of ADAM9 in HCT116 cells, which have a stable diploid karyotype suitable for omics analyses. Using this approach, we uncovered major signaling pathways downstream of ADAM9, including the oncogenic mTOR pathway and the tumor suppressor FOXO pathway. We also identified several direct and indirect substrates for ADAM9, which may mediate the pathophysiological roles of this protease. This study provides new mechanistic insights into the function of ADAM9 as well as a method that can be applied to other membrane proteases.

biochemistry↗

bioRxiv2024

Single-cell Landscape of Immune Cells in Blood and Skin in Psoriasis

BackgroundPsoriasis is a systemic inflammatory disease for which there is currently no cure, in part due to an incomplete understanding of its pathophysiology. MethodsTo better understand the immune response in psoriasis, we performed single-cell RNA sequencing (scRNA-seq) on peripheral blood mononuclear cells (PBMCs) and on lesional and non-lesional skin samples from a cohort of 11 psoriasis patients and 8 healthy controls. Additionally, we conducted flow cytometry on PBMCs from a separate cohort of 13 psoriasis patients and 11 ankylosing spondylitis. FindingsOur study revealed altered immune signatures of specific myeloid and lymphocyte subsets in blood and skin, both in terms of cell numbers and gene expression. Specifically, we discovered elevated proportions of circulating CD14++ monocytes, increased expression of major histocompatibility complex (MHC) class II molecule by circulating CD16+ monocytes, as well as increased expression of genes related to skin homing and to pro-inflammatory responses in psoriasis by circulating plasmacytoid dendritic cells (pDCs). Circulating CD8+ T effector memory cells in psoriasis patients exhibited reduced abundance but increased skin-homing potential. In psoriatic lesions, we observed a hyperinflammatory myeloid-cell state and enrichment of IL17-producing cells with a tissue-resident memory T-cell signature. InterpretationThe changes in immune cell numbers and gene expression indicate a significant alteration in the immune landscape of psoriasis patients. This suggests that the immune system in psoriasis is reprogrammed, affecting both innate and adaptive branches. These findings provide new insights into the aberrant immune-cell signatures in the circulation and skin lesions in psoriasis, and thereby help to understand its pathophysiology. FundingThis study was financially supported by the National Natural Science Foundation of China (U23A6012), Science and Technology Planning Project of Guangzhou (2024A03J0055, 202206080005), Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine (ZYYCXTD-C-202204).

systems biology↗

bioRxiv2024

A circular engineered sortase for interrogating histone H3 in chromatin

Reversible modification of the histone H3 N-terminal tail is critical in regulating chromatin structure, gene expression, and cell states, while its dysregulation contributes to disease pathogenesis. Understanding the crosstalk between H3 tail modifications in nucleosomes constitutes a central challenge in epigenetics. Here we describe an engineered sortase transpeptidase, cW11, that displays highly favorable properties for introducing scarless H3 tails onto nucleosomes. This approach significantly accelerates the production of both symmetrically and asymmetrically modified nucleosomes. We demonstrate the utility of asymmetrically modified nucleosomes produced in this way in dissecting the impact of multiple modifications on eraser enzyme processing and molecular recognition by a reader protein. Moreover, we show that cW11 sortase is very effective at cutting and tagging histone H3 tails from endogenous histones, facilitating multiplex "cut-and-paste" middle down proteomics with tandem mass tags. This cut-and-paste proteomics approach permits the quantitative analysis of histone H3 modification crosstalk after treatment with different histone deacetylase inhibitors. We propose that these chemoenzymatic tail isolation and modification strategies made possible with cW11 sortase will broadly power epigenetics discovery and therapeutic development.

biochemistry↗

bioRxiv2024

Design of linked-domain protein inhibitors of UBE2D as tools to study cellular ubiquitination

Ubiquitin (Ub) is a post-translational modification that largely controls proteostasis through mechanisms spanning transcription, translation, and notably, protein degradation. Ub conjugation occurs through a hierarchical cascade of three enzyme classes (E1, E2, and E3s) involving >1000 proteins that regulate the ubiquitination of proteins. The E2 Ub-conjugating enzymes are the midpoint, yet their cellular roles remain under-characterized, partly due to a lack of inhibitors. For example, the cellular roles of the promiscuous E2 UBE2D/UBCH5 are not well described. Here, we develop a highly selective, multivalent, engineered protein inhibitor for the UBE2D family that simultaneously targets the RING- and backside-binding sites. In HeLa cells, these inhibitors phenocopy knockdown of UBE2D by reducing the IC50 to cisplatin and whole-cell proteomics reveal an increased abundance of [~]20% of the identified proteins, consistent with reduced Ub degradation and proteotoxic stress. These precision tools will enable new studies probing UBE2Ds central role in proteome management.

biochemistry↗

bioRxiv2024

Allopolyploidy expanded gene content but not pangenomic variation in the hexaploid oilseed Camelina sativa

Ancient whole-genome duplications (WGDs) are believed to facilitate novelty and adaptation by providing the raw fuel for new genes. However, it is unclear how recent WGDs may contribute to evolvability within recent polyploids. Hybridization accompanying some WGDs may combine divergent gene content among diploid species. Some theory and evidence suggest that polyploids have a greater accumulation and tolerance of gene presence-absence and genomic structural variation, but it is unclear to what extent either is true. To test how recent polyploidy may influence pangenomic variation, we sequenced, assembled, and annotated twelve complete, chromosome-scale genomes of Camelina sativa, an allohexaploid biofuel crop with three distinct subgenomes. Using pangenomic comparative analyses, we characterized gene presence-absence and genomic structural variation both within and between the subgenomes. We found over 75% of ortholog gene clusters are core in Camelina sativa and <10% of sequence space was affected by genomic structural rearrangements. In contrast, 19% of gene clusters were unique to one subgenome, and the majority of these were Camelina-specific (no ortholog in Arabidopsis). We identified an inversion that may contribute to vernalization requirements in winter-type Camelina, and an enrichment of Camelina-specific genes with enzymatic processes related to seed oil quality and Camelinas unique glucosinolate profile. Genes related to these traits exhibited little presence-absence variation. Our results reveal minimal pangenomic variation in this species, and instead show how hybridization accompanied by WGD may benefit polyploids by merging diverged gene content of different species.

genomics↗

bioRxiv2024

Weed Instance Segmentation from UAV ortho-mosaic Images based on Deep Learning

Weeds significantly impact agricultural production, and traditional weed control methods often harm soil health and the environment. This study aims to develop deep learning-based segmentation models in identifying weeds in potato fields captured by Unmanned Aerial Vehicle (UAV) orthophotos and to explore the effects of weeds on potato yield. UAVs were used to collect RGB data from potato fields, flying at an altitude of 10m, with Real-ESRGAN Super-Resolution (SR) enhancing image resolution. We applied the Segment Anything Model (SAM) to do semi-automatic annotation, followed by training the YOLOv8 and MASK-RCNN models for segmentation. Also we used ANOVA and linear regression to analyze the effects of weeds and nitrogen fertilizer on yield. Results showed that the detection accuracy mAP50 scores for YOLOv8 and Mask R-CNN were 0.902 and 0.920, respectively, with the Real-ESRGAN-enhanced model achieving 0.909. When multiple weed types were present, accuracy decreased to 0.86. The linear regression model, incorporating plant and weed coverage areas, explained 41.2% of yield variation (R2 = 0.412, p-value = 0.01). Both YOLOv8 and Mask R-CNN achieved high accuracy, with YOLOv8 converging faster. Real-ESRGAN reconstruction slightly improved accuracy. Different nitrogen fertilizer treatments had no significant effect on yield, while weed control treatments significantly impacted yield, showing the importance of precise weed mapping.. This study provides insights into weed segmentation and contributes to environmentally friendly precision weed control. Graphic Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=108 SRC="FIGDIR/small/607729v1_ufig1.gif" ALT="Figure 1"> View larger version (45K): org.highwire.dtl.DTLVardef@40492org.highwire.dtl.DTLVardef@1c847b8org.highwire.dtl.DTLVardef@1dcb53corg.highwire.dtl.DTLVardef@fe96e5_HPS_FORMAT_FIGEXP M_FIG C_FIG

ecology↗

bioRxiv2024

Site-resolved energetic information from HX/MS experiments

High-resolution energetic information about protein conformational ensembles is essential for understanding protein function, yet remains challenging to obtain. We present PIGEON-FEATHER, a method for calculating ensemble free energies of opening ({Delta}Gop) at single- or near-single-amino acid resolution for proteins of all sizes from hydrogen exchange/mass spectrometry (HX/MS) data. PIGEON-FEATHER disambiguates and reconstructs all experimentally measured HX/MS isotopic mass envelopes using a Bayesian Monte Carlo sampling approach. We applied PIGEON-FEATHER to reveal how E. coli and human dihydrofolate reductases (ecDHFR, hDHFR) have evolved distinct ensembles. We show how two competitive inhibitors bind these orthologs differently, solving the longstanding mystery of why both therapeutic molecules inhibit hDHFR, but only one inhibits ecDHFR. Extending PIGEON-FEATHER to a large protein-DNA complex, we mapped ligand-induced ensemble reweighting in the E. coli lac repressor to describe the functional switching mechanism crucial for transcriptional regulation.

biophysics↗

bioRxiv2024

Mapping Genetic Interactions of All Paralogs in the Human Genome

Paralogs are abundant in the human genome and thought to be a primary source of synthetic lethality, yet the vast paralogome remains largely uncharacterized. A digenic screen of all paralogous gene pairs in the human genome revealed that synthetic lethalities were infrequent and varied in penetrance in different tumor backgrounds. We hypothesized that the variable penetrance of synthetic lethalities resulted from complex polygenic interactions with different cellular contexts. A machine learning classifier of a subset of paralog pairs tested across 49 cancer models revealed that endogenous perturbations in related pathways predicted paralog synthetic lethality. Further, predictive modeling of paralog synthetic lethality revealed that the strength of synthetic lethal interactions were largely due to the overlap and essentiality of the protein-protein interaction networks shared by the paralogs pairs. Collectively, this study tested all digenic paralog interactions and delineated the key feature classes that underlie the heterogeneity of paralog synthetic lethalities. HighlightsO_LISynthetic lethal paralogs have long been known, yet most paralog interactions are untested. C_LIO_LIWe report the first combinatorial screen of all 36,648 known human paralog pairs. C_LIO_LIA meta-analysis of 461 paralog pairs in 49 cell models revealed context-dependent interactions. C_LIO_LIThe essentiality of paralog interaction networks dictate the strength of synthetic lethality. C_LI eTOCSynthetic lethal paralogs have long been known, yet most paralog interactions are untested. Flister et al report a screen of all 36,648 known human paralog pairs. These data combined with a meta-analysis of 461 pairs across 49 cell models revealed insights to the molecular underpinnings of context-dependent synthetic lethality. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=195 SRC="FIGDIR/small/603642v3_ufig1.gif" ALT="Figure 1"> View larger version (61K): org.highwire.dtl.DTLVardef@1356ac3org.highwire.dtl.DTLVardef@1f43108org.highwire.dtl.DTLVardef@bf2a26org.highwire.dtl.DTLVardef@6844f8_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2024

BOOST: a robust ten-fold expansion method on hour-scale

Expansion microscopy (ExM) enhances the microscopy resolution by physically expanding biological specimens and improves the visualization of structural and molecular details. Numerous ExM techniques and labeling methods have been developed and refined over the past decade to cater to specific research needs. Nonetheless, a shared limitation among current protocols is the extensive time required for sample processing, particularly for challenging-to-expand biological specimens (e.g., formalin-fixed paraffin-embedded (FFPE) sections and large three-dimensional specimens). Here, we have developed a rapid and robust ExM workflow named BOOST, which leverages a series of novel microwave (MW)-accelerated ExM chemistry, resulting in a single-step linear expansion of [~]10x. Specifically, BOOST facilitates a [~]10-fold expansion of cultured cells, tissue sections, and even the challenging-to-expand FFPE sections under merely 90 minutes with heat and surfactant-based protein denaturation. Furthermore, BOOST employs microwave-assisted proteomic staining and immunostaining to facilitate high-resolution visualization of structural and molecular details with significantly enhanced throughput. Noteworthily, BOOST has pioneered a [~]10-fold expansion of large millimeter-sized three-dimensional specimens in approximately three hours. BOOST offers an easily adaptable workflow based on stable and common reagents, thus boosting the potential adoption of ExM methods in biological investigations.

bioengineering↗

bioRxiv2024

Hormonal dynamics reveal a stimulatory role for secretoneurin in zebrafish ovulation

Surge release of luteinizing hormone (Lh) from the pituitary is essential for fertility as it triggers ovulation. While secretoneurin (SN) is a phylogenetically conserved secretogranin-2 derived peptide that stimulates Lh, its role in ovulation has not been established. To directly compare periovulatory changes in the classical hormones to the emerging reproductive neuropeptides SNa and SNb, simultaneous mass spectrometry measurement of 9 peptides and 5 steroids was conducted in female zebrafish. Regression analysis indicated that levels of SNa1-34 in the brain peaked when type 3 gonadotropin-releasing hormone (Gnrh3) increased (R2=0.71) at the time of the Lh surge, 3.5 h before ovulation. In contrast, levels of the naturally occurring derivative SNa1-14 were highest at ovulation, while SNb1-31 was invariable. The bioactivities of SNa1-34 and SNa1-14 were investigated. After injection of SNa1-34 in females that had been isolated from males, 61% (11/18) ovulated within 6 h, which was like the effects of the Lh analog human chorionic gonadotropin (hCG) (72%; 13/18 females). SNa1-34 could induce ovulation by stimulating time-dependent expression of gnrh3 in the brain, chorionic gonadotropin alpha (cga), luteinizing hormone b (lhb) subunit in pituitary, and the nuclear progesterone receptor (npr) in ovaries. In contrast, SNa1-14 exhibited far fewer effects on gene expression and did not induce ovulation. Our results support the proposal that SN is a reproductive hormone. Significance statementSecretogranin-2 is a secretory granule protein that is enzymatically processed to the bioactive neuropeptide secretoneurin. It is produced in hypothalamic neurons and anterior pituitary cells, and we provide in vivo evidence that secretoneurin plays an important role to induce ovulation. Secretoneurin levels in the brain increase concomitantly with gonadotropin-releasing hormone prior to ovulation in normal zebrafish. Injection of a synthetic secretoneurin peptide increased expression of reproduction-related genes at all levels of the hypothalamic-pituitary-ovarian axis. Secretoneurin stimulates ovulation in otherwise anovulatory females. Together these data place the evolutionarily conserved secretoneurin amongst other critical neuroendocrine regulators. Secretoneurin or synthetic agonists could be used to improve breeding in fish species, or to potentially help with infertility treatments

physiology↗

bioRxiv2024

Comprehensive multimodal and multiomic profiling reveals epigenetic and transcriptional reprogramming in lung tumors

Epigenomic mechanisms are critically involved in mediation of genetic and environmental factors that underlie cancer development. Histone modifications represent highly informative epigenomic marks that reveal activation and repression of gene activities and dysregulation of transcriptional control due to tumorigenesis. Here, we present a comprehensive epigenomic and transcriptomic mapping of 18 tumor and 20 non-neoplastic tissues from non-small cell lung adenocarcinoma patients. Our profiling covers 5 histone marks including activating (H3K4me3, H3K4me1, and H3K27ac) and repressive (H3K27me3 and H3K9me3) marks and the transcriptome using only 20 mg of tissue per sample, enabled by low-input omic technologies. Using advanced integrative bioinformatic analysis, we uncovered cancer-driving signaling cascade networks, changes in 3D genome modularity, and differential expression and functionalities of transcription factors and noncoding RNAs. Many of these identified genes and regulatory molecules showed no significant change in their expression or a single epigenomic modality, emphasizing the power of integrative multimodal and multiomic analysis using patient samples.

genomics↗