Biology subjects

Weng, H.

Publications and source records attributed to Weng, H..

13 recordsLinked to original sources

bioRxiv2026

Transient suppression of the ECM1 gatekeeper is essential for HGF/c-MET-driven liver regeneration

Hepatocyte growth factor (HGF) is a multifunctional cytokine stored in the extracellular matrix as an inactive precursor and is essential for tissue repair. How HGF activity is dynamically regulated during regeneration remains unclear. Here, we identify extracellular matrix protein 1 (ECM1) as a physiological inhibitor of active HGF during liver regeneration. Following 70% partial hepatectomy, active HGF rapidly increases in parallel with a sharp decline in ECM1, and preventing this downregulation delays liver mass recovery. Mechanistically, ECM1 directly binds the active HGF -subunit through a mechanism dependent on residue R392, thereby suppressing c-MET-ERK-MYC signaling and hepatocyte proliferation. Loss of ECM1 permits activation of this pathway, whereas MYC overexpression rescues ECM1-mediated growth inhibition. In patients, proliferative hepatocytes localize to ECM1-negative regions. Supported by transcriptomic analyses and computational modeling, these findings identify ECM1 as an extracellular gatekeeper whose transient downregulation enables HGF-driven tissue repair. HighlightsO_LIECM1 is temporally downregulated during liver regeneration, while forced ECM1 expression delays liver mass recovery after 70% PHx by suppressing hepatocyte proliferation. C_LIO_LIRapid and transient ECM1 downregulation permits HGF-c-Met-ERK-MYC signaling to drive hepatocyte cell-cycle entry and expansion. C_LIO_LIECM1 directly binds the active HGF -subunit with residue R392 playing a critical role, revealing a novel extracellular mechanism for growth factor inhibition. C_LIO_LILoss of ECM1 marks proliferative hepatocytes in human liver repair, identifying ECM1 as a tunable regulator of regenerative capacity. C_LI

cell biology↗

bioRxiv2026

DNMT mRNA stability and YB-1 cooperatively regulate ABCB1 to drive cisplatin chemoresistance in cholangiocarcinoma

Background and AimsIntrahepatic cholangiocarcinoma (iCCA) is a tumor type with a high lethality due to late diagnosis and profound resistance to conventional chemotherapy. To date the molecular mechanisms underlying multidrug resistance remain poorly defined. Here, we integrate single-cell transcriptomics, clinicopathological analysis, and functional genomics to elucidate the molecular basis of cisplatin resistance in iCCA. Approach and ResultsSingle-cell RNA sequencing of iCCA and adjacent liver tissues revealed pronounced expression of Y-box-binding protein 1 (YB-1) in aneuploid malignant cholangiocarcinoma cells, with YB-1 expression progressively increasing during malignant evolution and strongly associated with chemoresistance. Clinically, elevated YB-1 expression-particularly its nuclear localization-robustly predicts poor overall survival and chemotherapy failure in patients with iCCA. Mechanistically, we demonstrate that cisplatin induces phosphorylation-dependent nuclear translocation of YB-1, enabling direct transcriptional activation of the drug efflux transporter ABCB1. Importantly, this process requires ABCB1 promoter demethylation, which is driven by cisplatin-induced, mA-dependent destabilization of DNMT1 and DNMT3B mRNAs. This destabilization occurs through disruption of the YB-1-IGF2BP1/3-DNMT mRNA stabilizing complex and subsequent recruitment of DNMT transcripts to YTHDF2-mediated processing bodies for degradation. ConclusionsOur findings uncover a previously unrecognized YB-1-mA-DNMT regulatory axis that drives chemotherapeutic resistance in iCCA, highlighting YB-1 as both a prognostic biomarker and a promising therapeutic target.

molecular biology↗

bioRxiv2025

Uranium mining fuels evolution in deep groundwater microbiomes

Deep-biosphere microbes have been underpinning global biogeochemical cycles throughout Earth history, yet their evolutionary responses to long-term anthropogenic disturbance remain poorly understood. Neutral-pH in-situ leaching (ISL), the dominant uranium-mining strategy, imposes persistent radiochemical and redox stress offering rare natural experiments across decades for observing subsurface microbial evolution. Here, by exploiting metagenomics and metatranscriptomics in examining microbial responses through various mining stages, we show that neutral U ISL causes substantial changes in microbial communities spanning 2,294 strains accompanied by diversification and selection of active microbial species. These changes occurred during elevated dissolved uranium and radiological activity which correlated with a substantial transcriptional change in energy metabolism, and with an overexpression of specific genes for oxidative-stress defence and DNA-repair pathways. Increased nucleotide diversity in 101 out of 392 species clusters and nonsynonymous/synonymous polymorphism ratios greater than one in 139 species clusters were predominantly observed in metatranscriptomes with elevated radiation, highlighting positive selection of transcriptionally active populations. These findings demonstrate that neutral U ISL drives functional and genetic diversification of subsurface microbiomes, revealing a dynamic and evolutionarily responsive deep biosphere.

genomics↗

bioRxiv2025

Regulation of essential hepatocyte functions and identity by super-enhancers in health and disease

Physiologically, hepatocytes perform an estimated 500 essential liver functions to ensure systemic homeostasis. The mechanisms how hepatocytes maintain these numerous crucial functions in response to physiological and pathophysiological challenges are largely unknown. In this study, we found that vital liver function genes (e.g., HNF4A, ALB, coagulation factors, and SLC2A2) in hepatocytes possess super-enhancers. Interfering with the super-enhancers by dCas9-sgRNA remarkably decreases the expression of these genes. Quiescent liver progenitor cells (LPCs) do not have active super-enhancers in vital liver function genes. In acute liver failure (ALF) caused by massive hepatic necrosis, activated LPCs perform liver function and differentiate into hepatocytes to rescue patients lives. We show that activated LPCs gradually form super-enhancers in liver function genes (e.g., HNF4A, ALB, and coagulation factors) during proliferation and differentiation. These super-enhancers are regulated by FOXA2 through the recruitment of HNF4 a, p300 and Mediators in most liver function genes, such as ALB and coagulation factors. However, super-enhancers in some genes (e.g., SLC2A2) are FOXA2-indenpendent. Hepatic FOXA2 expression is closely associated with the clinical outcome of ALF. In a cohort of ALF patients, robust FOXA2 is observed only in the surviving patients. Collectively, super-enhancers represent a critical epigenetic regulatory mechanism that enables rapidly enhanced transcription of liver function genes in response to pathophysiological challenges. In urgent clinical syndrome such as ALF, LPCs rescue liver function by rapid formation of super-enhancers in vital genes.

molecular biology↗

bioRxiv2024

Deletion of Zyxin Reduces Endothelial Inflammation and Mitigates Atherosclerosis

BACKGROUNDOscillatory shear stress (OSS)-induced endothelial inflammation plays a critical role in the pathogenesis of atherosclerosis. However, the involvement of endothelial zyxin, a mechanosensor, in OSS-associated atherosclerosis and its underlying mechanisms remains unclear. METHODSTo investigate the role of zyxin in vivo, ZyxiniECKOApoE-/- mice were utilized in atherosclerosis model induced by carotid artery ligation; in vitro, endothelial cells were subjected to disturbed flow in Ibidi systerm. RESULTSZyxin was significantly upregulated in the OSS regions of both human and mouse arteries. The specific deletion of zyxin in endothelial cells (ECs) in ApoE-/- (ZyxiniECKOApoE-/-) mice reversed the ECs activation and atherosclerosis induced by OSS. In vitro studies indicated that the absence of zyxin reduced the induction of adhesion molecules and pro-inflammatory cytokines stimulated by OSS. Mechanistic investigations demonstrated that 14-3-3{beta} facilitated yes-associated protein (YAP) phosphorylation at Serine 127, which played a critical role in retaining YAP within the cytoplasm. Under OSS stimulation, zyxin inhibited the phosphorylation of YAP at Serine 127 through its interaction with 14-3-3{beta}, rather than direct regulation of YAP. This inhibition enhanced YAPs nuclear translocation and promoted endothelial inflammation. Furthermore, it was shown that rosuvastatin inhibited zyxin expression in human umbilical vein endothelial cells and the vascular endothelium of ApoE-/- mice. This inhibition led to decreased levels of inflammatory markers and adhesion molecules associated with atherosclerotic lesions observed in the partially ligated left common carotid arteries of ApoE-/- mice. CONCLUSIONSThis study further confirms that zyxin is a mechanoreceptor in endothelial cells and elucidates the indispensable role of the zyxin-14-3-3{beta}-YAP axis in endothelial inflammation and atherogenesis. This indicates that Zyxin plays a crucial role in protecting against atherosclerosis.

cell biology↗

bioRxiv2024

Retinoic acid generates a beneficial microenvironment for liver progenitor cell activation in acute liver failure

ObjectiveWhen massive necrosis occurs in acute liver failure (ALF), rapid expansion of hepatic stem cells called liver progenitor cells (LPC) in a process called ductular reaction (DR) is required for survival. The exact underlying mechanisms of this process are not known to date. In ALF, high levels of retinoic acid (RA), a molecule known for its pleiotropic roles in embryonic development, are secreted by activated hepatic stellate cells (HSCs). We hypothesized that RA plays a key role during DR in ALF. MethodsRNA-Seq was performed to identify molecular signaling pathways affected by all-trans retinoid acid (atRA) treatment in HepaRG LPC cells. Functional assays for RA were performed in HepaRG cells with atRA treatment as well as co-culture with LX-2 cells in vitro, and liver tissue of patients suffering from ALF in vivo. ResultsUnder ALF conditions, activated HSCs secreted RA, inducing RAR nuclear translocation in LPCs. RNA-seq data and investigations in HepaRG cells revealed that atRA treatment activated the WNT-{beta}-Catenin pathway, enhanced stemness genes (SOX9, AFP, et.al), promoted energy storage, and elevated the expression of ATP-binding cassette (ABC) transporters depending on RAR nuclear translocation. Further, atRA treatment-induced pathways were confirmed in a co-culture system of HepaRG with LX-2 cells. Patients with ALF who displayed RAR nuclear translocation in LPC had significantly better MELD scores than those without. ConclusionIn ALF, RA secreted by activated hepatic stellate cells promotes LPC activation, a prerequisite for subsequent LPC-mediated liver regeneration.

cell biology↗

bioRxiv2023

Extracellular Matrix Protein 1 Attenuates Hepatic Fibrosis by Inhibiting TSP-, ADAMTS-, and MMP-Mediated Latent TGF-β1 Activation

ObjectiveExtracellular Matrix Protein 1 (ECM1) serves as a gatekeeper of hepatic fibrosis by maintaining transforming growth factor-{beta}1 (TGF-{beta}1) in its latent form. ECM1 knockout (KO) causes latent (L) TGF-{beta}1 activation, resulting in hepatic fibrosis with rapid mortality. In chronic liver disease (CLD), ECM1 decreases with increasing CLD severity. We investigate the regulatory role of ECM1 in TGF-{beta}1 bioavailability and its impact on CLD progression. DesignRNAseq was performed to analyze hepatic gene expression. Functional assays were performed using hepatic stellate cells (HSCs), Ecm1-KO and Fxr-KO mice, patient liver tissue, and computer simulations. ResultsExpression of LTGF-{beta}1 activators, including thrombospondins (TSPs), ADAMTS proteases, and matrix metalloproteinases (MMPs) increased along with pro-fibrotic gene expression in liver tissue of Ecm1-KO mice. In HSCs, overexpression of ECM1 prevented TSP-1-, ADAMTS1-, and MMP-2/9-mediated LTGF-{beta}1 activation. In vitro interaction assays demonstrated that ECM1 inhibited LTGF-{beta}1 activation by interacting with TSP-1 and ADAMTS1 via their respective, intrinsic KRFK or KTFR amino acid sequences, and by suppressing MMP-2/9 proteolytic activity. In mice, ECM1 overexpression attenuated KRFK-induced LTGF-{beta}1 activation, while KTFR treatment reversed Ecm1-KO- and Fxr-KO-mediated liver injury. In patients with CLD, ECM1 expression was inversely correlated with TSP-1, ADAMTS1, MMP-2/9 expression and LTGF-{beta}1 activation. And these results were complemented by a computational compartment model representing the key network of cellular phenotypes and predicted interactions in liver fibrogenesis. ConclusionOur findings underscore the hepatoprotective effect of ECM1, which interferes with mediators of LTGF-{beta}1 activation, suggesting ECM1 or its representative peptide as potential anti-fibrotic therapies in CLD. What is already known on this topic?[tpltrtarr] ECM1 expression is negatively correlated with CLD progression. [tpltrtarr]ECM1 maintains liver homeostasis by keeping TGF-{beta}1 latency. What this study adds?[tpltrtarr] ECM1 inhibits LTGF-{beta}1 activation through interfering with key activators, including TSP-1, ADAMTS1, MMP-2, and MMP-9. [tpltrtarr]ECM1 interacts with TSP-1 and ADAMTS1 via their respective, intrinsic KRFK or KTFR amino acid motifs, and suppresses MMP-2/9 proteolytic activity. [tpltrtarr]In vivo, ECM1 overexpression mitigates KRFK peptide-induced LTGF-{beta}1 activation, while KTFR peptide rescues Ecm1-KO- and Fxr-KO-induced liver injury. [tpltrtarr]ECM1 expression inversely correlates with TSP-1, ADAMTS1, MMP-2/9 expression and LTGF-{beta}1 activation in CLD patients. How might this study affect research, practice or policy?[tpltrtarr] Considering severe adverse effects associated with anti-fibrotic treatments utilizing TGF-{beta}1 receptor inhibitors, our findings indicate that restoration of ECM1 expression or phenocopying peptides might represent a novel and safe route to urgently needed anti-fibrotic therapies in CLD.

cell biology↗

bioRxiv2023

FOXA2 is essential for maintaining the urea cycle in acute liver failure

Hepatic encephalopathy is a lethal complication of acute liver failure (ALF), and is caused by hyperammonemia. Ammonia clearance by the liver requires an intact and complete urea cycle comprising six enzymes, including the rate-limiting enzyme carbamoyl phosphate synthetase I (CPS1). To date, the detailed regulation of CPS1 transcription in order to maintain urea cycle in physiological condition and ALF remains largely unknown. This study scrutinizes the role of pioneer factor forkhead box A 2 (FOXA2) in the regulation of CPS1 transcription, urea cycle performance and hyperammonemia. Physiologically, CPS1 transcription requires FOXA2 to maintain chromatin accessibility on its enhancers, which is essential for CCAAT enhancer-binding protein-alpha (C/EBP) binding to activate gene transcription. In ALF, hepatic C/EBP expression is inhibited by inflammatory mediators such as TGF-{beta} and TNF-. In this setting, retinoic acid receptor synergizes with FOXA2 to maintain CPS1 transcriptions. Once ALF patients suffer from massive hepatic necrosis, liver progenitor cells initiate a transcription network comprising FOXA2 and C/EBP to perform the urea cycle and prevent hyperammonemia. In ALF, hepatic encephalopathy occurs in patients lacking hepatic FOXA2 expression. In mice with acetaminophen-induced ALF, injection of Foxa2-AAV8 maintains urea cycle and prevents hyperammonemia. Taken together, FOXA2 is essential for maintaining the urea cycle. Pharmaceutical induction of hepatic FOXA2 expression might represent a novel approach to treat hepatic encephalopathy in ALF. One Sentence SummaryPioneer factor FOXA2 synergizes with C/EBP or RAR to maintain urea cycle in acute liver failure

molecular biology↗

bioRxiv2023

Rapid dexamethasone treatment inhibits LPS-induced cytokine storm in mice

Severe infection-induced cytokine storm is an urgent medical syndrome with high mortality. To date, no therapy is available. This study shows that high concentrations of lipopolysaccharide (LPS) induce cytokine storm within 48h and thus kill most experimental mice. Rapid, but not late dexamethasone administration remarkably inhibits cytokine storm and rescues LPS-treated mice. Monocytes and macrophages are the major source of cytokine storm. In these cells, pro-inflammatory genes (i.e., Tnf, Il6 and Il1{beta}) have preassembled RNA polymerase II (RNA Pol II), but stay at the pause stage of transcriptional elongation in the absence of stimulation. LPS rapidly activates transcription of these "pre-loaded" genes within 2h. Administration of dexamethasone within this time window inhibits RNA Pol II ser2 binding to the core promoters of pro-inflammatory genes and thus reduces LPS-induced cytokine transcription. Therefore, rapid utilization of dexamethasone might be efficacious to prevent severe bacterium-induced cytokine storm in clinical practice.

molecular biology↗

bioRxiv2021

Regeneration of spinal motor axons: Negative regulation by Celsr2 implicating Cdc42/Rac1 and JNK/c-Jun signaling

During development, cadherins Celsr2 and Celsr3 control axon navigation. Unlike Celsr3, Celsr2 remains expressed in the adult, suggesting unexplored roles in maintenance and repair. Here we show that Celsr2 knockdown promotes motor axon regeneration in mouse and human spinal cord explants and cultured motor neurons. Celsr2 downregulation is accompanied by increased levels of GTP-bound Rac1 and Cdc42, and of JNK and c-Jun proteins. Using a branchial plexus injury model, we show that forelimb functional recovery is improved in Celsr2 mutant versus control mice. Compared to controls, in mutant mice, reinnervated biceps muscles are less atrophic, contain more newly formed neuromuscular junctions, and generate larger electromyographic potentials, while motor neuron survival and axon regeneration are improved. GTP-bound Rac1 and Cdc42, JNK and c-Jun are upregulated in injured mutant versus control spinal cord. In conclusion, Celsr2 negatively regulates motor axon regeneration via Cdc42/Rac1/JNK/c-Jun signaling and is a target for neural repair.

neuroscience↗

bioRxiv2020

Fine-scale Population Structure and Demographic History of Han Chinese Inferred from Haplotype Network of 111,000 Genomes

ABSTRACTHan Chinese is the most populated ethnic group across the globe with a comprehensive substructure that resembles its cultural diversification. Studies have constructed the genetic polymorphism spectrum of Han Chinese, whereas high-resolution investigations are still missing to unveil its fine-scale substructure and trace the genetic imprints for its demographic history. Here we construct a haplotype network consisted of 111,000 genome-wide genotyped Han Chinese individuals from direct-to-consumer genetic testing and over 1.3 billion identity-by-descent (IBD) links. We observed a clear separation of the northern and southern Han Chinese and captured 5 subclusters and 17 sub-subclusters in haplotype network hierarchical clustering, corresponding to geography (especially mountain ranges), immigration waves, and clans with cultural-linguistic segregation. We inferred differentiated split histories and founder effects for population clans Cantonese, Hakka, and Minnan-Chaoshanese in southern China, and also unveiled more recent demographic events within the past few centuries, such as Zou Xikou and Chuang Guandong. The composition shifts of the native and current residents of four major metropolitans (Beijing, Shanghai, Guangzhou, and Shenzhen) imply a rapidly vanished genetic barrier between subpopulations. Our study yields a fine-scale population structure of Han Chinese and provides profound insights into the nation’s genetic and cultural-linguistic multiformity.Competing Interest StatementThe authors AL, KK, ST, XW, LW, TL, HW, JD, QZ, XY, and GC work for WeGene (Shenzhen Zaozhidao Technology Co. Ltd. or Shenzhen WeGene Clinical Laboratory).View Full Text

genomics↗

bioRxiv2019

WDR76 promotes MLL-rearranged leukemia via selective recognition of 5-hydroxymethylcytosine in DNA

Although rare, the distribution of the 5-hydroxymethylcytosine (hmC) modification in mammalian DNA is tissue- and gene-specific, yet distinct from its transcriptionally-repressive methylcytosine (mC) precursor, suggesting unique signaling potential. To examine this possibility, we fractionated mammalian brain extracts to discover binding partners specific for oxidized states of mC. We demonstrate that one such factor, WDR76, is a highly hmC-specific binding protein that modulates gene expression within chromosomal regions enriched in hmC where it binds. We demonstrate direct transcriptional activation of several target genes in mouse embryonic stem cells as a function of hmC levels and contingent upon WDR76. In human cell lines and mouse models, WDR76 recruitment by hmC is critical for the initiation and maintenance of MLL-rearranged leukemias. Beyond its canonical role as an intermediate in mC remediation, we show that hmC can be an epigenetic mark whose recognition drives leukemogenesis, portending analogous signaling pathways for other rare DNA modifications.

biochemistry↗

bioRxiv2018

A statistical framework for cross-tissue transcriptome-wide association analysis

Transcriptome-wide association analysis is a powerful approach to studying the genetic architecture of complex traits. A key component of this approach is to build a model to predict (impute) gene expression levels from genotypes from samples with matched genotypes and expression levels in a specific tissue. However, it is challenging to develop robust and accurate imputation models with limited sample sizes for any single tissue. Here, we first introduce a multi-task learning approach to jointly impute gene expression in 44 human tissues. Compared with single-tissue methods, our approach achieved an average 39% improvement in imputation accuracy and generated effective imputation models for an average 120% (range 13%-339%) more genes in each tissue. We then describe a summary statistic-based testing framework that combines multiple single-tissue associations into a single powerful metric to quantify overall gene-trait association at the organism level. When our method, called UTMOST, was applied to analyze genome wide association results for 50 complex traits (Ntotal=4.5 million), we were able to identify considerably more genes in tissues enriched for trait heritability, and cross-tissue analysis significantly outperformed single-tissue strategies (p=1.7e-8). Finally, we performed a cross-tissue genome-wide association study for late-onset Alzheimers disease (LOAD) and replicated our findings in two independent datasets (Ntotal=175,776). In total, we identified 69 significant genes, many of which are novel, leading to novel insights on LOAD etiologies.

genetics↗