Biology subjects

Gao, C.

Publications and source records attributed to Gao, C..

At least 37 records · Page 2Linked to original sources

bioRxiv2026

First Metagenome-Assembled Genomes from the Historic Morrow Plots Reveal Management-Associated Dominance of Archaeal Ammonia Oxidizers

Soil microbial communities underpin both soil health and agricultural productivity, yet genome-resolved resources from long-term field experiments remain limited. Here, we present a genome-resolved metagenomic dataset from the historic Morrow Plots long-term experiment in central USA, comprising 33 shotgun metagenomes collected across diverse crop rotation and fertilization treatments in year 149 of the experiment. Using a co-assembly, multi-binner workflow, we recovered 230 metagenome-assembled genomes (MAGs), including 44 archaeal and 186 bacterial genomes spanning multiple soil-associated phyla. Among these, 59 MAGs were linked to nitrogen-cycling functions, including ammonia- and nitrite-oxidizing lineages. The dataset also includes genome quality metrics, taxonomic classification, and treatment-resolved abundance patterns across different management regimes. Importantly, these nitrogen guild MAGs enable comparative analyses of nitrifier ecology, genome diversity, and functional variation linked to management in agricultural soils. Together, these resources establish a unique benchmark for studying how agricultural practices shape soil microbial communities at genome level, with associated long-term crop yield and soil fertility changes since the experiments inception in 1876.

microbiology↗

bioRxiv2026

Stelar starch management tailors diurnal and rehydration-related water flows in Pinus pinea needles

Pine needles contain two vascular cell types unique to gymnosperms: Transfusion parenchyma (tp) and tracheids (tt). Since they form the only connections between vascular bundles and bundle sheath, we hypothesised that they are involved in regulating the needles water import and photoassimilate export. Synchrotron-based tomography enabled us to quantify volume changes of tp and tt cells in Pinus pinea needles systematically along the needle and throughout a diurnal day cycle, as well as under rehydration. As a physiological indicator of tps carbohydrate status served their starch content. Segmentation of the comprehensive data uncovered dramatic volume changes during dehydration and showed a diurnal course of starch formation and degradation. These changes suggest a yet unknown osmotic water flux between tp and tt, balanced by the formers carbohydrate status. Confirming our hypothesis, excess of photoassimilates in tp cells went into starch synthesis during the day. Starch mobilisation during the night increased the osmotic potential in tp and led to water intake. According to the decreasing starch fraction from base to needle tip, this mechanism is predominant in the upper needle segments, particularly after rehydration of dehydrated needles. Mechanistically, osmolytes in tp cells maintain tension in tt for the needles water import. HighlightSynchrotron tomographic microscopy uncovers diurnal starch fluctuations and osmotic water pumping in inner tissues of pine needles that are utilised at night and when recovering from dehydration

plant biology↗

bioRxiv2026

Arborist: Prioritizing Bulk DNA Inferred Tumor Phylogenies via Low-pass Single-cell DNA Sequencing Data

Cancer arises from an evolutionary process that can be reconstructed from DNA sequencing and modeled by tumor phylogenies. High coverage bulk DNA sequencing (bulk DNA-seq) is widely available, but tumor phylogeny inference requires deconvolution, often resulting in non-uniqueness in the solution space. Single-cell DNA sequencing (scDNA-seq) holds potential to yield higher resolution tumor phylogenies, but the sparsity of emerging low-pass sequencing technologies poses challenges for the study of single-nucleotide variants. Increasing availability of data sequenced with both modalities provides an opportunity to capitalize on the advantages of these technologies. While inference methods exist for bulk DNA-seq and for low-pass scDNA-seq, no joint inference methods currently exist. As a first step, we propose a method named ARBORIST that prioritizes tumor phylogenies inferred via bulk DNA-seq using low-pass scDNA-seq data. ARBORIST takes as input a candidate set of trees with corresponding SNV clustering, along with variant and total read count data from scDNA-seq and uses variational inference to approximate a lower bound on the marginal likelihood of each tree in the candidate set. On simulated data, matching characteristics of current scDNA-seq data, ARBORIST outperforms both bulk and low-pass single-cell reconstruction methods. On a biological dataset, ARBORIST conclusively resolves the evolutionary relationship between different SNV clusters on a malignant peripheral nerve sheath tumor, which is supported by orthogonal validation via a proxy for copy number. ARBORIST provides a principled framework for integrating bulk DNA-seq and low-pass scDNA-seq data, improving confidence in tumor phylogeny reconstruction. Availabilityhttps://github.com/VanLoo-lab/Arborist

bioinformatics↗

bioRxiv2026

Evolutionary dynamics of insect odorant receptors reveal ecological tuning shaping olfactory perception

Insect olfaction is facilitated by a heterotetrameric odorant receptor-odorant receptor co-receptor (OR-Orco) complex, which is distinct from that of vertebrate ORs. However, extreme sequence divergence among insect ORs has hindered a unified understanding of their evolutionary history and ecological importance. In this study, we present a multiscale analysis of OR genes across 115 insect species. We overcome the limitations of traditional phylogenetic approaches by applying a protein similarity network-based strategy and introduce a "trunk-branch" framework to systematically describe the evolutionary trajectories of insect ORs across sequence, structural, and predicted olfactory potential levels. Although they possess different sequences and structural communities, all sampled insect orders contained ORs assigned to all six docking-derived functional communities. Notably, extant insect lineages with order-level origins spanning the end-Permian mass extinction (EPME) differed in docking-derived functional OR repertoires, and early-and late-diverging lineages differed in OR sequence-community diversity. The emergence of Orco represents a key evolutionary transition point, marking the shift from a homomeric to a heteromeric complex accompanied by specialization of the extracellular domain and binding pocket. Furthermore, we established robust associations between potential olfactory recognition breadth and ecological variables, including diet, circadian rhythm, and habitat. Our findings provide a class-level framework for investigating insect OR evolution and generate testable hypotheses about how receptor repertoire diversification may relate to ecological adaptation.

evolutionary biology↗

bioRxiv2026

A novel uN2CpolyG Transgenic Mouse Model Recapitulates Multisystemic polyG Proteinopathy Pathology of Neuronal Intranuclear Inclusion Disease

Neuronal intranuclear inclusion disease (NIID) is a polyglycine disease that primarily affects the neuronal and neuromuscular systems. Here, we developed a novel transgenic mouse model that faithfully recapitulates the multisystemic impairments associated with polyG intranuclear inclusions. Our findings demonstrate that polyG expression induces neurodegeneration, behavioral deficits, and age-dependent accumulation of uN2CpolyG aggregates across multiple tissues.

animal behavior and cognition↗

bioRxiv2026

An agentic framework turns patient-sourced records into a multimodal map of ALS heterogeneity

ALS progression is multidimensional, yet fragmented records and scalar outcomes obscure how patients move through disease states and how those states relate to molecular variation. MEDSTREM converts patient-held medical-record images into standardised longitudinal data, enabling bottom-up cohort construction. Using MEDSTREM-structured records from more than 8,000 AskHelpU participants together with PRO-ACT and Answer ALS, we developed DynaALS, the ALS Disease Dynamics Atlas. DynaALS represents ALS as a dynamic patient-state manifold that captures distinct directions of deterioration and patient movement between them over time. DynaALS retrieved population-referenced future states and decoded them into multidimensional clinical profiles without requiring patient-specific longitudinal histories. Motor-neuron RNA and chromatin profiles linked DynaALS states to developmental and regulatory programs, while neuromuscular-organoid single-cell multi-omics converged on a neural-developmental Netrin-DCC signalling axis across interacting cell types. By coupling MEDSTREM-enabled data construction to dynamic state modelling, DynaALS establishes a transferable patient-state engine for predictive and biologically interpretable disease models.

bioinformatics↗

bioRxiv2026

Analytic Bounds on GAMLSS Model Variability of Normative White Matter Brain Charts

Brain charts, or normative models of quantitative neuroimaging measures, can identify trajectories of brain development and abnormalities in groups and individuals by leveraging large populations. Recent work has extended these brain charts to model microstructural and macrostructural features of white matter. Assessments of variance for these brain charts are necessary to determine whether the models being used for these data are stable. We implement an analytic approach to characterize variability of the parameters in previously released brain charts created using the generalized additive models for location, scale, and shape (GAMLSS) framework. Additionally, we empirically validate the accuracy of each analytic model through a comparison to a bootstrapping approach from 0.2 to 90 years of age. We find that across all models, the analytic coefficient of variation (COV) remains below 5% for ages greater than 0.25 years, with the maximum empirical observed COV reaching 7% at 0.2 years of age. Further, the empirical assessment shows high agreement with the analytic assessment, with COV estimates averaged across the lifespan for all models having a Pearson correlation coefficient of 0.776 and a mean difference of 4 x 10-4. Both methods exhibit volume and surface area as the features with the largest average COV for the majority of tracts. However, the analytic assessment yields axial diffusivity as the feature most frequently having the smallest COV, whereas the corresponding feature for the empirical assessment is average length. These results suggest that the analytic approach overestimates model stability for WM brain charts when the COV is low and that the validation method is suitable for assessing whether GAMLSS models are unstable.

bioengineering↗

bioRxiv2026

A distal CTCF-binding site drives MYC expression plasticity in a negative feed-forward loop

Oncogene expression heterogeneity systemically diversifies cancer cell phenotypes, enabling selection and cancer evolution. Here we document that the level of MYC expression variation is coordinated by a negative feed-forward loop involving the non-coding CCAT1 eRNA and the MYC gating process. While CCAT1 eRNA indirectly antagonizes MYC gating by promoting MYC transcriptional initiation and elongation, the MYC protein promotes gated MYC expression in a feedback loop by inhibiting both MYC transcription and CCAT1 expression. This entire process is coordinated by a CTCF binding site positioned within CCAT1 at a distal, oncogenic super-enhancer, which functions as a master switch by coordinating both CCAT1 and gated MYC expression to diversify cells toward both low and high MYC levels, as determined by heterogeneity metrics. As hallmarks of this principle are frequent in breast cancer and colorectal tumors, the dynamics of this new principle may underlie transitions between therapy-resistant low-MYC, and proliferative high-MYC tumor cells. Highlights- Transcriptional rate regulates MYC gating frequency - CCAT1 expression indirectly inhibits MYC gating by promoting MYC transcription - High MYC protein levels promote gated expression by inhibiting both MYC transcription and CCAT1 expression - These features are controlled by a single CTCF binding in the distant super-enhancer to drive expression plasticity in colorectal cancer cells

cancer biology↗

bioRxiv2025

Fibroblasts sense spatial proximity via an EGFR CREB5 axis to restore quiescent synovial lining in remission rheumatoid arthritis

Rheumatoid arthritis (RA) is a chronic inflammatory disease where the synovial lining membrane undergoes pathological changes resulting in joint destruction. In healthy joints, the synovial lining is essential for joint homeostasis, forming a selective barrier and secreting lubricating molecules, yet the mechanisms that restores homeostatic synovial lining during RA remission remains poorly understood. Here, we applied spatial transcriptomics to examine biopsies of RA patients in remission to identify a mechanism that orchestrates a phenotypic switch specifying synovial quiescent lining fibroblast differentiation. Spatial transcriptomics revealed a proximity-sensing program where at low cell-density, fibroblasts adopt proliferative and fibrotic transcriptional state characterized by expression of MKI67, COL1A2 and COL6A2, whereas at high cell-density, fibroblasts induce a quiescent lining fibroblast transcriptional program characterized by PRG4, CLU and PDPN. Mechanistically, fibroblasts sense spatial proximity through HB-EGF-EGFR signaling, which leads to phosphorylation of transcription factor CREB5. Perturbation of the EGFR-CREB5 axis abolishes fibroblast proximity-sensing and blocks synovial lining fibroblast differentiation. Conversely, EGFR activation by the ligand HB-EGF or pharmacologic activation of CREB5 is sufficient to induce synovial lining fibroblast differentiation. Together, our findings define a novel spatial proximity-sensing pathway underlying a return to homoeostatic fibroblast function during RA remission. By sensing their spatial proximity to neighboring fibroblasts, synovial fibroblasts translate these positional cues into signals that lead to restoration of normal, steady-state synovial lining membrane.

genomics↗

bioRxiv2025

Epithelial FOXP3 Drives Pancreatic Fibrosis through O-glycosylated IL-6

BACKGROUND & AIMSThe transcription factor FOXP3, known for specifying regulatory T cell fate, is unexpectedly expressed in the epithelium of precancerous pancreatic lesions. Here we investigate its non-immune role in initiating pancreatic fibrosis, a process driving therapeutic resistance and organ failure in pancreatic ductal adenocarcinoma (PDAC) with unknown origins in early neoplasia. METHODSUsing human tissues and genetically engineered mouse models, we analysed FOXP3 expression in premalignant lesions. We employed epithelial-specific FOXP3 knockout and knock-in strategies to determine its functional impact on fibrogenesis and neoplasia progression. Mechanistic studies included chromatin immunoprecipitation, glycomic analyses, and signalling assays. RESULTSFOXP3 was consistently expressed in the epithelial compartment of human and murine precancerous pancreas. Epithelial-specific deletion of FOXP3 attenuated pancreatic fibrosis and delayed neoplasia, whereas its knock-in induced spontaneous stromal activation and accelerated PanIN progression. Mechanistically, epithelial FOXP3 directly transactivated the glycosyltransferase GALNT1. GALNT1, in turn, mediated O-glycosylation of interleukin (IL)-6, which was essential for its rapid secretion. CONCLUSIONSOur study establishes epithelial-derived FOXP3 as a master regulator of early pancreatic fibrocarcinogenesis. It drives a glycosylation-dependent amplification loop for IL-6 signalling, orchestrating sustained stromal activation. This pathway represents a promising target for intercepting pancreatic fibrosis and carcinogenesis at its origin.

cancer biology↗

bioRxiv2025

Spatial Transcriptomics Identify T Cell-Driven Mechanisms of Kidney Damage in Immune Checkpoint Inhibitor-Associated Acute Interstitial Nephritis

IntroductionImmune checkpoint inhibitor-associated acute interstitial nephritis (ICI-AIN) is the most common finding on histopathology among patients with ICI-associated acute kidney injury (ICI-AKI). Patients with ICI-AIN often have T cell-dominant infiltration of the kidney and high tissue levels of CXCR3 ligands like CXCL9, 10, and 11; however, the mechanisms of inflammation in ICI-AIN are not well-understood. MethodsWe applied a sub-cellular spatial transcriptomics platform (Xenium Prime 5K) to compare the cellular composition of kidney biopsy tissue from patients with ICI-AIN with ICI-treated patients with acute tubular necrosis (ICI-ATN). ResultsAcross 8 kidney biopsy specimens (4 with ICI-AIN, 4 with ICI-ATN), we analyzed 332,000 cells, comprising kidney parenchymal cells and infiltrating immune cells. Using a spatially-aware cellular neighborhood-based classification, we identified cellular niches corresponding to each part of the nephron, in addition to unique fibrotic and inflammatory niches. Gene pathway analysis identified interferon-gamma (IFN-{gamma})/STAT1 signaling as strongly increased in ICI-AIN compared to ICI-ATN. While all inflammatory niches were overrepresented in ICI-AIN, CD8+ T cell infiltration and proinflammatory myeloid cells were the dominant immune niches. Spatial niche crosstalk analysis revealed that CD8+ T cell-derived IFN-{gamma} likely induced a proinflammatory program in myeloid cells, with increased production of CXCL9, 10, and 11. Furthermore, IFN-{gamma} signaling in ICI-AIN was associated with reduced oxidative phosphorylation in kidney tubular niches. ConclusionsSpatial transcriptomics reveal novel insights into key differences in the pathophysiology of ICI-AIN versus ICI-ATN. IFN-{gamma}-producing CD8+ T cells are likely key drivers of ICI-AIN and should be investigated as future therapeutic targets. Translational StatementSpatial transcriptomics may provide insight into differences in the cellular and spatial composition of immune checkpoint inhibitor-associated acute interstitial nephritis (ICI-AIN) and ICI-associated acute tubular necrosis (ICI-ATN). Using the novel Xenium 5K platform, we demonstrate that IFN-{gamma}-producing CD8+ T cells are central to the pathogenesis of ICI-AIN, and that CD8+ T cell-derived IFN-{gamma} likely induces a proinflammatory state in myeloid cells, with increased tissue production of CXCL9, 10, and 11. We then show that a reduction in oxidative phosphorylation and an IFN-{gamma}-driven influx of proinflammatory myeloid cells may further drive kidney damage in ICI-AIN. Many of these pathways represent potential druggable targets, and our findings may therefore inform future therapeutic approaches for ICI-AIN.

immunology↗

bioRxiv2025

Chronic sensing of host-derived lipids is an all-in-one signal that primes and activates NLRP3.

Activation of the NLRP3 inflammasome leads to the production of bioactive interleukin (IL)-1{beta} fostering atherosclerosis. The current dogma is that NLRP3 must be first primed by microbial stimuli, known as pathogen-associated molecular patterns (PAMPs), and then activated by either microbial or host-derived inflammatory cues. The mechanism that controls NLRP3 functioning in the context of non-communicable diseases lacking overt microbial infections remains debated. Here, we show that chronic exposure to atherosclerosis-associated oxidized phospholipids (oxPLs) simultaneously primes and activates NLRP3 independently of microbial cues. Mechanistically, chronic exposure to host-derived oxPLs activate the transcription factor NRF2, which is necessary and sufficient to prime and activate NLRP3 in a PAMP-independent manner. NRF2 chronic activation drives oxidized mitochondrial DNA to activate NLRP3. Ex vivo analyses of atherosclerotic plaques in mice and humans identify a population of monocytes-derived macrophages which activates NRF2 and expresses IL-1{beta}. Overall, our data point to oxPL-dependent NRF2 activation as an all-in-one signal necessary and sufficient to prime and activate NLRP3, sustaining atherogenesis.

immunology↗

bioRxiv2025

MYRF is Essential for Epicardial Development

Myelin Regulatory Factor (MYRF) is a transcription factor previously known for myelination of neurons in the central nervous system. Accumulating evidence has recently implicated MYRF mutations in the pathogenesis of cardiac urogenital syndrome (CUGS), in which patients exhibit a range of cardiac abnormalities, including atrial septal defect (ASD), ventricular septal defect (VSD), and hypoplastic left heart syndrome (HLHS). However, the mechanisms by which MYRF deficiency leads to cardiac anomalies remain poorly defined. Moreover, in part due to the lack of cell-type specific loss-of-function models, it is unclear which cardiac cell types contribute to the defects observed in MYRF-related CUGS. To address these questions, we examined the expression pattern of MYRF in the heart and found that it is most highly expressed in epicardial cells (EPCs) among all cardiac cell types. Importantly, Myrf global knockout (KO) mice displayed impeded epicardial development, with markedly reduced epicardial coverage of the myocardial surface. Furthermore, specifically deleting MYRF in EPCs results in severely degenerated epicardium, dramatically reduced epicardial derived cells (EPDCs), and thin myocardial wall. Conversely, ablating MYRF in cardiomyocytes (CMs) did not lead to any overt cardiac phenotypes, indicating that MYRF is dispensable for the developing CMs. Taken together, our findings suggest that compromised function of MYRF in EPCs may contribute to the pathogenesis of MYRF-related CUGS. To our knowledge, this is the first study to link impaired epicardial development to this disease.

developmental biology↗

bioRxiv2025

Lifespan Trajectories of Asymmetry in White Matter Tracts

Asymmetry in white matter is believed to give rise to the brains capacity for specialized processing and is involved in the lateralization of various cognitive processes, such as language and visuo-spatial reasoning. Although studies of white matter asymmetry have been previously documented, they have often been constrained by limited age ranges, sample sizes, or the scope of the tracts and structural features examined. While normative lifespan charts for brain structures are emerging, comprehensive charts detailing white matter asymmetries across numerous pathways and diverse structural measures have been notably absent. This study addresses this gap by leveraging a large-scale dataset of 35,120 typically developing and aging individuals, ranging from 0 to 100 years of age, from 50 primary neuroimaging studies. We generated comprehensive lifespan trajectories for 30 lateralized association and projection white matter tracts, examining 6 distinct microstructural and macrostructural features of these pathways. Our findings reveal that: (1) asymmetries are widespread across the brains white matter and are present in all 30 pathways; (2) for a given pathway, the degree and direction of asymmetry differ between features of tissue microstructure and pathway macrostructure; (3) asymmetries vary across and within pathway types (association and projection tracts); and (4) these asymmetries are not static, following unique trajectories across the lifespan, with distinct changes during development, and a general trend of becoming more asymmetric with increasing age (particularly in later adulthood) across pathways. This study represents the most extensive characterization of white matter asymmetry across the lifespan to date, charting how lateralization patterns emerge, mature, and change throughout life. It provides a foundational resource for understanding the principles of white matter organization from early to late life, its relation to functional specialization and inter-individual variability, and offers a key reference for interpreting deviations during healthy development and aging as well as those associated with clinical populations.

neuroscience↗

bioRxiv2025

Directed evolution of a compact TranC11a system for efficient genome editing

The recently discovered TranC systems represent programmable RNA-guided DNA endonucleases of transposon origin with compact protein sizes ideal for therapeutic delivery. However, their editing efficiency in human and plant cells is limited. Here, we evolved TranC11a and engineered its sgRNA to enhance overall editing efficiencies. TranC11a systems exhibit up to 9.2-fold higher editing activity than its parent and achieves efficiency comparable to SpCas9 across multiple human genome endogenous sites, significantly outperforming compact editors NovaIscB and enTnpB1c. TranC11a enables efficient editing of disease-relevant genes in human cells and breeding traits in maize. With its high editing activity and compact size (574 aa), TranC11a demonstrates strong potential for future in vivo genome editing and crop engineering.

synthetic biology↗

bioRxiv2025

Discovery of A Small Molecule non-IMiD Degrader of ZBTB7A for the Treatment of β-hemoglobinopathies

Sickle cell disease and {beta}-thalassemia, two major {beta}-hemoglobinopathies, pose significant clinical challenges globally. Current treatments often face limitations in efficacy and tolerability. The transcription factor ZBTB7A has emerged as a promising therapeutic target for reactivating fetal hemoglobin expression. Here, we report the discovery and characterization of SH6, a small molecule non-IMiD degrader of ZBTB7A. SH6 induces fetal hemoglobin in erythroid cell lines in a CRBN and ZBTB7A-dependent manner, and it is capable of inducing fetal hemoglobin expression in healthy donor, SCD and {beta}-thalassemia patient CD34+ cell derived erythroid cells. The efficacy of SH6 is confirmed in a xenotransplantation humanized mouse model. SH6 outperforms currently available therapeutic agents in vitro, and shows synergy with hypomethylating agents. SH6 exhibits a favorable in vivo toxicity profile. Our findings establish SH6 as a promising therapeutic lead candidate for further optimization towards clinical development for treatment of sickle cell disease and {beta}-thalassemia.

cell biology↗

bioRxiv2025

Semaglutide drives weight loss through cAMP-dependent mechanisms in GLP1R-expressing hindbrain neurons

Glucagon-like peptide 1 receptor (GLP1R) agonists like semaglutide drive weight loss through the brain, but insights into their intracellular signaling mechanisms are lacking. Although canonically GLP1Rs signal through the stimulatory alpha Gs protein, we find that semaglutide utilizes both Gs- and Gq-signaling pathways in GLP1Rs in the area postrema (AP)--the primary site of semaglutide action in the brain--to differentially regulate neuronal activation across distinct neuronal clusters. Semaglutide also drives graded increases of the essential secondary messenger cyclic adenosine monophosphate (cAMP) in Glp1r-expressing AP neurons (APGlp1r) through Gs-dependent and -independent manners. Inhibition of the cAMP-degradation enzyme phosphodiesterase 4 (PDE4) can enhance and sustain these cAMP responses, whereas disruption of Gs or cAMP signaling in APGlp1r neurons abolishes semaglutide-induced weight loss and downstream brain-wide activation. Our systematic characterization of semaglutides signaling mechanisms in the brain provides avenues for improving the performance of obesity therapeutics.

neuroscience↗

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↗