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Zhang, Q.

Publications and source records attributed to Zhang, Q..

At least 181 records · Page 10Linked to original sources

A neural network model of free recall learns multiple memory strategies

Humans exhibit structured patterns of memory recall, including a tendency to recall more recent information and to recall events in the same order they were experienced. Classic computational models explain these patterns by positing that memories incorporate the ongoing "temporal context", formed by smoothly integrating the stimulus history. However, it is unclear whether a single mechanism can account for the full repertoire of human memory strategies, as the optimal approach may be task-dependent. For example, human memory experts widely apply the "memory palace" strategy, which is empirically better but not captured by temporal context models. Here we show that neural networks optimized for free recall develop diverse retrieval strategies, with only some of them resembling temporal context models. The best-performing models discovered a stimulus-invariant index code that emphasizes the studied position of each list item, instead of its temporal context. This creates a stable scaffold for forward recall akin to the memory palace technique. This index code was more likely to emerge when networks were i) encouraged to recall all studied items rather than prioritizing only the next few items, and ii) prevented from relying on recency. Our findings demonstrate that human-like recall patterns can arise from multiple distinct computational mechanisms, and that sequential retrieval using item index is an optimal strategy that explains expert-level recall performance.

neuroscience↗

Human SerRS/SIRT2 complex structure reveals cross regulation between translation and NAD+ metabolism

Life at the cellular level depends on effective coordination between diverse processes. Here we uncover a novel cross-regulation between metabolism and translation through a 3.2 [A] cryo-EM structure of human cytosolic seryl-tRNA synthetase (SerRS) bound to sirtuin-2 (SIRT2), an NAD+-dependent deacetylase. This interaction, naturally triggered by the NAD+ metabolite ADP-ribose (ADPR), resembles substrate binding and block SIRT2s active site. Interestingly, SerRS acetylation is not required for this interaction. SIRT2 binding sterically and allosterically impedes tRNA binding to SerRS, lowering charged tRNASer level and protein synthesis activity. Key interaction residues in both proteins emerged simultaneously in vertebrates, suggesting co-evolution for cross-regulation. Given ADPRs accumulation under stress, the ADPR-induced SerRS/SIRT2 interaction likely serves as a cell-protective response.

molecular biology↗

Deciphering acquired resistance mechanisms to sustained auxin-inducible protein degradation in cells and mice

Targeted protein degradation is a favorable strategy for studying the immediate downstream effects of protein loss-of-function. An appealing platform among these technologies is the auxin-inducible degron (AID) system. Although this system has been applied extensively to cell and animal models, degradation resistance to long-term auxin treatment has not been studied. With the advent of the new AID2 system, cellular toxicity due to the high concentrations of auxin required in the original AID1 system is no longer a concern, making it possible to study protein degradation over extended periods. In this study, we derived multiple miniAID-tagged knock-in human cell lines and a Ctcf-miniAID knock-in mouse strain to investigate mechanisms of degradation resistance. We revealed four independent resistance mechanisms, including a nonsense mutation in the CTCF coding sequence that removed the miniAID peptide, a missense point mutation in the miniAID coding region that disrupted ubiquitin complex targeting, and silencing of the OsTIR1 adaptor protein. Resistance to auxin degradation was also acquired in mouse primary CtcfminiAID/miniAID knock-in B-ALL cells through missense mutations of the OsTIR1(F74G) protein in vivo and ex vivo. In summary, our innovative study expands our understanding of the AID system and cautions careful consideration of design for future applications in mammalian system.

cell biology↗

ADAMTS3 as a promising novel biomarker for the diagnosis of hepatocellular carcinoma

Early diagnosis of hepatocellular carcinoma (HCC) still represents a significant challenge. The rising of obesity and non-viral liver disease associated HCC further limits the effectiveness of conventional screening approaches such as ultrasonography and alpha-fetoprotein (AFP) testing. In this context, the identification of potential effective biomarkers for rapid and precise diagnosis of HCC still represents an extremely important task. Here, we identify ADAMTS3 as a novel mechanistic serum biomarker for HCC that addresses this shifting etiological landscape. Transcriptome analysis of four independent cohorts-including HCC patients, individuals with obesity-or non-viral liver disease, and healthy controls- reveals four secreted proteins associated with HCC progression. Among them, ADAMTS3 demonstrates strong diagnostic performance by ROC (receiver operating characteristic) and LASSO (least absolute shrinkage and selection operator) analysis. High ADAMTS3 expression correlates with aggressive molecular signature, characterized by enhanced proliferative signaling, suppressed immune effector responses, and a reprogrammed immune microenvironment marked by reduced NK cell infiltration and increased accumulation of immunosuppressive tumor-associated macrophages, driven by extracellular matrix stiffening. Knockdown of ADAMTS3 in cell lines significantly reduced proliferation, and clonogenic potential. Reintroduction of ADAMTS3 partially rescued both phenotypes, further confirming its role in promoting HCC cell growth. Optical tweezer-based measurements further reveal reduced cell stiffness upon ADAMTS3 deficiency, highlighting its role in extracellular matrix (ECM) remodeling. Finally, to provide a simple strategy for HCC diagnosis based on this novel biomarker, we demonstrated a DNA origami-based SERS biosensor capable of detecting ADAMTS3 at 10-11 M. Together, these findings identify ADAMTS3 as a mechanistic biomarker and demonstrate a translational sensing strategy for non-invasive HCC early screening.

cancer biology↗

Analysis of Nutritional Components in Brown Sugar and Its Effects on Anti-fatigue, Alleviation of Qi Deficiency and Blood Stasis, and Antioxidant Effects

Brown sugar (BS), Red granulated sugar (RGS) and White sugar(WS) are three key sweeteners and food additives in China. Notably, BS possesses significant nutritional value and has been widely used in Chinese medicine for its supportive therapeutic properties.This study evaluated the anti-fatigue, the amelioration of qi deficiency and blood stasis, as well as the antioxidant activities of these sugars using a zebrafish model. BS and RGS demonstrated significantly greater efficacy than WS in terms of both anti-fatigue effects and amelioration of qi Deficiency and blood stasis in the zebrafish model. Antioxidant assays revealed that BS, RGS, and WS (500 g/mL) significantly enhanced superoxide dismutase (SOD) activity in zebrafish embryos compared with the control group. Furthermore, the mineral composition of sugar were determined. Nine mineral elements--potassium (K), calcium (Ca), sodium (Na), magnesium (Mg), iron (Fe), zinc (Zn), copper (Cu), phosphorus (P), and selenium (Se)--were analyzed. BS exhibited markedly higher concentrations of P, Ca, Fe, and Mg than RGS and WS, while selenium (detected at 50 mg/kg) was exclusively detected in BS. Intriguingly, RGS contained four-fold higher potassium levels than BS. Total polyphenol content, quantified by Folin-Ciocalteu assay, was 4.35 g/kg in BS and 1.53 g/kg in RGS, with no detectable polyphenols in WS.

biochemistry↗

Spatial predictive coding in visual cortical neurons

Predictive coding is a theoretical framework that can explain how animals build internal models of their sensory environments by predicting sensory inputs. Predictive coding may capture either spatial or temporal relationships between sensory objects. While the original theory by Rao and Ballard, 1999 described spatial predictive coding, much of the recent experimental data has been interpreted as evidence for temporal predictive coding. Here we directly tested whether the "mismatch" neural responses in sensory cortex are due to a spatial or a temporal internal model. We adopted two common paradigms to study predictive coding: one based on virtual-reality and one based on static images. After training mice with repeated visual stimulation for several days, we performed multiple manipulations, including: 1) we introduced a novel stimulus, 2) we replaced a stimulus with a novel gray wall, 3) we duplicated a trained stimulus, or 4) we altered the order of the stimuli. The first two manipulations induced a substantial mismatch response in neural populations of up to 20,000 neurons recorded across primary and higher-order visual cortex, while the third and fourth ones did not. Thus, a mismatch response only occurred if a new spatial - not temporal - pattern was introduced.

neuroscience↗

Structure and Function of Lens Suture Examined by 2-photon Fluorescence Microscopic Imaging

We have applied 2-photon fluorescence microscopy (2PFM) to investigate the structures and functions of mouse eye lenses, especially lens sutures, using wildtype (WT) and KLPH-KO suture-cataract lenses in vivo. Dynamic structures of lens sutures have been hypothesized to act as pathways carrying fluid containing ions, nutrients, and other factors as part of microcirculation for maintaining lens homeostasis and transparency. 3D imaging results show both typical "Y" and "double Y" shaped suture structures in WT lenses, diverse suture patterns including "star" shapes with variations appearing at different depths, and misaligned suture planes in KLPH-KO lenses. The variability in suture patterns, quantified using the mean of image stacks similarity indices (SSIM) to the mean projection of the stack, reveals a significant increase (p<0.05) in pattern randomization for KLPH-KO lenses. Both WT and KLPH-KO lenses exhibit voids around sutures and enlarged vacuoles throughout the lens structure in vivo. Pathological features like irregular and larger central voids containing 2~5-{micro}m-diameter amorphous structures that might result from membrane protein remnants/aggregates in the KLPH-KO mouse eye lens were observed. In conclusion, this work provides new morphological markers for characterizing suture cataract and fiber pathological features. Lens sutures are stabilized structures that are impermeable to dyes, and the extracellular spaces of lens peripheral fibers provide efficient diffusion pathways for lens microcirculation.

biophysics↗

Unveiling the Human Nasopharyngeal Microbiome Compendium: Systematic Characterization of Community Architecture and Function Through a Comprehensive Meta-Analysis

The nasopharyngeal microbiome is critical for respiratory health, yet its compositional architecture remains largely uncharacterized, underlying conflicting reports of increased, decreased, or unchanged diversity during infection. Here, we demonstrate that these contradictions arise from a fundamentally overlooked factor: the nasopharynx is organized into six reproducible nasopharyngeal community state types (NPCSTs) that are associated with intrinsic diversity baselines independent of disease status. By uniformly reprocessing 7,790 16S rRNA gene sequencing samples from 28 studies, we show that NPCSTs explain 52% of community variance, four-fold more than study effects, and that disease-diversity associations are attenuated by over 92% after NPCST adjustment. To identify genuine disease markers, we applied NPCST-aware differential abundance testing to SARS-CoV-2 as a case study. Leave-one-study-out (LOSO) cross-validation across 10 cohorts confirmed 13 reproducible taxa with opposing shifts: obligate anaerobes typically studied in other body compartments were enriched, while resident hub genera were depleted with high directional consistency across LOSO iterations. Co-occurrence network analysis independently validated this pattern, identifying the depleted taxa as structural backbone hubs across all NPCSTs. To bridge microbiome ecology and clinical application, we developed the Nasopharyngeal Microbiome Health Index (NMHI), a continuous community-level wellness score achieving AUC of 0.90 and 0.92 in internal and external validations, respectively, with robust performance across all six NPCSTs (AUC: 0.848-0.953). An independent clinical cohort of 147 specimens confirmed that these NPCST and NMHI characteristics are reproducible. Unlike binary classifiers, NMHI quantifies nasopharyngeal health along a spectrum, establishing NPCST-aware analysis as a foundation for precision respiratory microbiome research.

bioinformatics↗

The MEK inhibitor trametinib incurs mitochondrial injury and induces innate immune responses in the mouse heart

Trametinib (Trm) is a highly selective MEK inhibitor that potently and persistently abrogates ERK1/2 activation. Trm initially was used to treat BRAF V600E-mutated melanoma but its FDA-approved indications are expanding rapidly. Trm generally is well tolerated but it can cause dose-limiting cardiomyopathy and heart failure. Here we characterize a mouse model of Trm cardiotoxicity using complementary in vitro approaches to show that Trm induces mitochondrial dysfunction in cardiomyocytes and some cancer cell types. In vivo, Trm caused contractile dysfunction within 3 days and heart failure within 2 weeks. High resolution respirometry using isolated cardiac mitochondria revealed that Trm compromises oxidative metabolism, in part through blunted activity of Electron Transport System Complexes. Trm-mediated mitochondrial injury led to the release of mitochondrial Damage-Associated Molecular Patterns including mitochondrial DNA in both mice and humans, triggering activation of canonical innate immune pathways including cGAS-STING. In multiple rodent and human cardiomyocyte platforms, Trm diminished mitochondrial respiratory capacity at nanomolar concentrations but this lesion was reversed by expression of a phosphomimetic STAT3-S727 construct. We also found that Trm induced mitochondrial dysfunction in some but not all cancer cell lines, identifying a previously unrecognized effect that could contribute to Trms anti-cancer efficacy.

physiology↗

Hypoimmunogenic human motor neurons induced from iPSCs in vivo substantially ameliorate ALS disease in large animal models

Stem cell-based therapy holds great potential for substituting degenerated motor neurons (MNs) in amyotrophic lateral sclerosis (ALS). Missing protocols for advanced differentiation of transplanted cells into MNs, immune rejection, and the lack of suitable ALS models for preclinical trials have slowed the development of effective therapies. Here, we employed multiplex genetic-editing to generate a novel human pluripotent stem cell line containing doxycycline (Dox)-inducible MNs-specific transcription factors and comprehensively modified immunomodulatory genes. We transplanted these cells into the spinal cord of ALS large animal models (SOD1G93A pigs and TIA1P362L rabbits), which faithfully recapitulate pathologies and symptoms observed in ALS patients. The transplanted cells could efficiently differentiate into functional MNs upon Dox treatment in vivo, distribute throughout the spinal cord and motor cortex via extensive migration, survive long-term without the need for immunosuppression. Notably, these MNs integrated into host neural circuits, as evidenced by their long projection of peripheral axons to target muscle and reformation of neuromuscular junctions. As result, pathologies and motor deficits were substantially ameliorated in both animal models. One Sentence SummaryHypoimmunogenic human motor neurons induced from iPSCs in vivo reform neuromuscular junctions and ameliorate ALS disease in pig and rabbit models.

neuroscience↗

Real-Time Viability Assessment of Ex Vivo Mouse Kidneys for Transplant Applications Using Dynamic Optical Coherence Tomography

Kidney transplantation remains the preferred treatment for patients with end-stage kidney disease. However, the ongoing shortage of donor organs continues to limit the availability of transplant treatments. Existing evaluation methods, such as the kidney donor profile index (KDPI) and pre-transplant donor biopsy (PTDB), have various limitations, including low discriminative power, invasiveness, and sampling errors, which reduce their effectiveness in organ quality assessment and contribute to the risk of unnecessary organ discard. In this study, we explored the dynamic optical coherence tomography (DOCT) as a real-time, non-invasive approach to monitor the viability of ex vivo mouse kidneys during static cold storage over 48 hours. The dynamic metrics logarithmic intensity variance (LIV), early OCT correlation decay speed (OCDSe), and late OCT correlation decay speed (OCDSl) were extracted from OCT signal fluctuations to quantify temporal and spatial tissue activity and deterioration. Our results demonstrate that DOCT provides complementary functional information to morphological assessment offered by conventional OCT imaging, showing potential to improve pre-transplant organ evaluation and clinic decision-making.

bioengineering↗

Mycobacterium tuberculosis m4C DNA methyltransferase Rv3204 promotes mycobacteria survival under oxidative stress

Reactive oxygen species (ROS) inflict cellular damage yet are pivotal mediators of signaling pathways. Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), persists as a major global health threat, partly due to its capacity to neutralize host-derived ROS toxicity. While DNA methylation deficiency is known to attenuate Mtb virulence, the specific role of DNA methyltransferases in mycobacterial survival under oxidative stress remains poorly defined. Here, we demonstrate that the mycobacterial protein Rv3204 functions as an N4-methylcytosine (m4C) DNA methyltransferase. Deletion of the Rv3204 homolog (Ms_1939) in Mycobacterium smegmatis significantly impaired bacterial survival upon rifampicin exposure. This phenotype was associated with heightened intracellular ROS accumulation and a failure to upregulate transcription of ROS detoxification genes. Furthermore, the mutant exhibited downregulated expression of DNA repair genes and increased susceptibility to fluoroquinolone antibiotics (norfloxacin, ofloxacin). Crucially, the Ms_1939 deletion strain displayed elevated levels of DNA damage. To our knowledge, this is the first study establishing a direct link between an m4C DNA methyltransferase and ROS homeostasis in mycobacteria. Our findings identify Rv3204 as a potential novel therapeutic target for modulating ROS sensitivity in M. tuberculosis. ImportanceMycobacterium tuberculosis, the causative agent of tuberculosis, remains a major global health threat due in part to its ability to withstand host-derived oxidative stress. This study identifies Rv3204 as a novel N4-methylcytosine DNA methyltransferase essential for mycobacterial survival under oxidative stress. We demonstrate that deletion of Rv3204 homolog in M. smegmatis leads to elevated intracellular ROS, impaired transcriptional activation of antioxidant and DNA repair genes, increased DNA damage, and heightened susceptibility to fluoroquinolone antibiotics. Our findings establish a critical link between epigenetic regulation via m4C methylation and ROS homeostasis in mycobacteria--a relationship previously unexplored. This work not only advances our understanding of bacterial epigenetic mechanisms in stress adaptation but also positions Rv3204 as a promising target for novel anti-tuberculosis strategies aimed at disrupting redox balance and enhancing antibiotic efficacy. DATA summaryRaw data files have been deposited in the National Center for Biotechnology Information (NCBI) Gene Expression Omnibus (GEO) under accession number GSE139646 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE139646).

genetics↗

CREG1 restricts ALV-J replication via the mitochondrial dysfunction-driven activation of innate immunity and apoptosis

Despite the implementation of purification strategies to partially limit J subgroup avian leukosis virus (ALV-J) infection, the involvement of host factors in the underlying infection mechanism remains largely undefined. Here, we identify cellular repressor of E1A-stimulated genes 1 (CREG1) as a key regulator of mitochondrial function and a critical immune-related gene involved in ALV-J infection. The objective of this study was to explore the effects and underlying mechanisms of CREG1 in the context of ALV-J infection. Overexpression of CREG1 upregulates the expression of type I interferon (I-IFN) and certain interferon-stimulated genes (ISGs), thereby suppressing viral replication. Mechanistically, overexpression of CREG1 induces mitochondrial dysfunction, characterized by a decrease in mitochondrial membrane potential ({Delta}{psi}m), reduced adenosine triphosphate (ATP) production and respiratory chain activity, enhanced mitophagy, and increased release of mitochondrial DNA (mtDNA), which in turn triggers the activation of innate immune responses. Mitochondrial dysfunction further leads to the cytosolic release of cytochrome c and an increase in reactive oxygen species (ROS) levels, thereby triggering a robust apoptotic response. Moreover, the regulation of mitochondrial function by CREG1 depends on its interaction with the mitochondrial chaperone protein heat shock protein 1 (HSPD1), and their co-expression synergistically amplifies the antiviral response. In this study, we identify CREG1 as a potent antiviral gene and underscore the pivotal roles of mitochondria-mediated innate immunity and apoptosis during ALV-J infection. Author summaryDespite efforts to limit J subgroup avian leukosis virus (ALV-J) infection, the role of host factors in the infection process is still not fully understood. In this study, we highlight the cellular repressor of E1A-stimulated genes 1 (CREG1) as a crucial regulator of mitochondrial function and immune responses during ALV-J infection. We show that CREG1 overexpression enhances type I interferon (I-IFN) and interferon-stimulated genes (ISGs) expression, inhibiting viral replication. This is achieved through mitochondrial dysfunction, including reduced mitochondrial membrane potential, lower ATP production, and increased mitophagy and mitochondrial DNA release, which activate innate immunity. CREG1-induced mitochondrial dysfunction also triggers apoptosis by releasing cytochrome c and increasing reactive oxygen species (ROS). Furthermore, CREG1 interacts with heat shock protein 1 (HSPD1) to amplify its antiviral effects. Our findings establish CREG1 as a key antiviral gene and emphasize the importance of mitochondrial-mediated immune responses and apoptosis in ALV-J infection.

immunology↗

Spatial Transcriptomics Reveal Developmental Dynamics of the Human Cerebral Cortex and Striatum

The human fetal brain undergoes morphological changes that contribute to the development of regional functionalities. However, the features of structural development, the underlying molecular and cellular signatures in the fetal brain remain unclear. With spatial transcriptomics and snRNA-seq, we identified 25 forebrain regions and characterized the dynamic changes in the cortex and striatum during the late first and early second trimesters. In particular, we discovered that temporal lobe enriched NPY-expressing L2/3 EX neuron potentially interacted with L4 EX neurons during cortical expansion and arealization. Additionally, the gyrus and sulcus were developmental asynchronous, in which HOPX and SPARC genes were potentially involved. Further investigation on the striatum showed specific genes and cell types that enriched in patch and matrix compartments, and SST-positive interneurons potentially involved in the development of these structures. Together, our results give insights into the understanding of early fetal brain development.

bioinformatics↗

Comparison and Dynamic interaction between Auditory Cortex and Prefrontal Cortex of Behaving Monkeys during Novelty Detection

The ability to detect deviations from expected sensory input is fundamental for adaptive behavior. We recorded electrocorticographic activity from the auditory (AC) and prefrontal (PFC) cortices of behaving macaques during an auditory oddball task to probe the cortical dynamics of predictive processing. Repetition of standard stimuli evoked suppression and facilitation in AC and strong low-frequency (2 Hz) enhancement in PFC, accompanied by bidirectional delta-band coupling indicative of a shared predictive state. Deviant stimuli triggered early AC responses followed by PFC activation and increased feedforward and feedback connectivity across delta, theta, and gamma bands. Behavioral engagement amplified both prediction and prediction error signals, strengthening cortical network coordination. Together, these findings reveal a hierarchical predictive network in which the AC encodes sensory regularities and violations, while the PFC integrates predictive context in a behaviorally dependent manner.

neuroscience↗

DNA Sequence Trace Reconstruction Using Deep Learning

Deciphering DNA sequences is fundamental to unlocking the mysteries of life, but the high dimensionality and complexity of biological sequence data significantly hinder knowledge discovery. In particular, the challenges of sequence length, repetitive regions, and structural complexity make it difficult to directly reconstruct complete DNA sequences from raw data. Therefore, this paper proposes a DNA sequence trace reconstruction model, DNARetrace, which performs preprocessing and dataset construction, and then employs a Bidirectional Fourier-Kolmogorov-Arnold Network (Bi-FKGAT), using an extremely unbalanced loss function for link prediction, so as to reconstruct the original DNA sequence. In multi-angle experiments using both simulated and real data, DNARetrace successfully reconstructs DNA sequence traces across large-scale datasets derived from various DNA sequencing methods, overcoming the bias of current approaches toward specific sequencing platforms, and achieves competitive outcomes in DNA storage and genomics downstream tasks. We further validated the expandability of the proposed methods in DNA sequence classification and metagenomic binning tasks. In summary, DNARetrace is compatible with various sequencing scenarios; it reduces the difficulty of discovering novelty knowledge directly from high-complexity raw data, and it provides a reusable tool to accelerate DNA sequence processing and applications.

genomics↗

Characterizing a hallmark of glymphatic insufficiency: Wasteosomes accumulate in periventricular white matter hyperintensities and exhibit complex relationships with mixed pathology, sclerotic index and perivascular space

The glymphatic system is a recently elucidated waste clearance system in the brain, thought to be critical for the maintenance of homeostasis. Corpora amylacea or "wasteosomes", are discontinuous lipid labyrinth structures that are polyglucosan rich, retain cellular waste and are thought to be of astrocytic origin. Wasteosomes have been proposed as a hallmark of glymphatic insufficiency predominantly due to: 1) their spatial localization around glymphatic drainage points including periventricular (PV) regions, perivascular spaces (PVS), and sub-pial regions; and, 2) their correlation with aging, vascular disorders, neurodegenerative diseases, and conditions that impair sleep. White matter hyperintensities (WMHs) are diffuse hyperintense areas seen on T2-weighted or fluid-attenuated inversion recovery (FLAIR) magnetic resonance imaging (MRI) scans that represent damage to white matter. PV WMHs and are known predictors of mild cognitive impairment, stroke, dementia and death. The relationship between wasteosome accumulation, PV WMHs, vascular pathology and PVS is currently unknown. For the first time, in a mixed diagnostic cohort of pathologically diagnosed: Alzheimers disease (AD), cerebrovascular disease (CVD), mixed AD/CVD, and control tissue with no pathological diagnosis, we connected the histopathological wasteosome profile in periventricular brain sections in relation to 7T FLAIR-MRI confirmed PV WMHs, vascular stenosis and PVS. Our results reveal wasteosomes accumulate in PV WMHs, are increased in proximity to large PV venules, and exhibit complex relationships with WMH severity, mixed pathology, sclerotic index and PVS. These findings suggest wasteosomes may serve as histological markers of impaired glymphatic drainage and provide new insights into the pathophysiology underlying white matter injury.

neuroscience↗

A scalable computational framework for predicting gene expression from candidate cis-regulatory elements

Deciphering the relationships between cis-regulatory elements (CREs) and target gene expression has been a long-standing unsolved problem in molecular biology, and the dynamics of CREs in different cell types make this problem more challenging. To address this challenge, we propose a scalable computational framework for predicting gene expression (ScPGE) from discrete candidate CREs (cCREs). ScPGE assembles DNA sequences, transcription factor (TF) binding scores, and epigenomic tracks from discrete cCREs into 3-dimensional tensors, and then models the relationships between cCREs and genes by combining convolutional neural network with transformer. Compared with current state-of-the-art models, ScPGE exhibits superior performance in predicting gene expression and yields higher accuracy in identifying active enhancer-gene interactions through attention mechanisms. By comprehensively analyzing ScPGEs predictions, we find a pattern in true positives (TPs) that the regulatory effect of cCREs on genes decreases with distance. Inspired by the pattern, we design two methods to enhance the ability to capture distal cCRE-gene interactions by incorporating chromatin loops into the ScPGE model. Furthermore, ScPGE accurately discovers some crucial TF motifs within prioritized cCREs and reveals the different regulatory types of these cCREs.

bioinformatics↗