Biology subjects

Zhu, C.

Publications and source records attributed to Zhu, C..

At least 145 records · Page 8Linked to original sources

bioRxiv2023

Personalized connectivity-based network targeting model of TMS for treatment of psychiatric disorders: computational feasibility and reproducibility

Consider the limited clinical efficacy of transcranial magnetic stimulation (TMS) due to heterogeneity in treatment outcomes, the utilization of individual functional connectivity (FC) can enhance the prediction accuracy in the network targeting model. However, the low signal-to-noise ratio (SNR) of FC poses a challenge when utilizing individual resting-state FC (rsFC). To overcome this challenge, proposed solutions include increasing the scan duration and employing clustering approaches to enhance the stability of FC. In this study, we aimed to evaluate the stability of a personalized functional-based network targeting model in individuals with major depressive disorder (MDD) and schizophrenia with auditory verbal hallucinations (AVH). Using resting-state functional magnetic resonance imaging (rsfMRI) data from the Human Connectome Project (HCP), we assessed the models stability and employed longer scan durations (7 minutes, 14 minutes, 21 minutes, 28 minutes) and clustering methodologies to improve the precision of identifying optimal individual sites. Our findings demonstrate that a scan duration of 28 minutes and the utilization of the clustering approach lead to stable identification of individual sites, as evidenced by the intraindividual distance falling below the [~]1cm spatial resolution of TMS. These findings contribute to the understanding of individualized TMS targeting and have implications for improving treatment outcomes in psychiatric disorders.

neuroscience↗

bioRxiv2023

Insights from the Early Cretaceous: The promise of Lycoptera aDNA sequencing

Obtaining high-quality ancient DNA (aDNA) is a crucial process for advancements in molecular paleontology. However, current research is restricted to a limited range of fossil types due to DNA degradation and contamination from environmental DNA (eDNA). Utilizing the technology of nanoparticle affinity beads, we successfully extracted DNA from Lycoptera davidi fossils and obtained 1,258,901 DNA sequences. To ascertain their origins, we developed and implemented a novel protocol, the "mega screen method", designed to categorize aDNA fragments. This approach successfully identified 243 Actinopterygii species-specific fragments (SSFs), which subsequent analysis confirmed as original in situ DNA (oriDNA) sequences. Lycoptera davidi, a ray-finned fish from the Early Cretaceous Jehol Biota, dates back approximately 120 million years (Ma). Notably, the absence of deamination in certain oriDNA and paleoenvironmental DNA (paeDNA) fragments calls into question its reliability as a definitive marker for aDNA identification, a phenomenon potentially attributable to the protective effects of fossil diagenesis. Additionally, we identified a novel mechanism, "coding region sliding replication and recombination", responsible for generating new transposase. This mechanism, distinct from conventional processes such as horizontal gene transfer or vertical inheritance from parents, can facilitate a rapid genomic diversification. The transposase CDS insertion into the GAS2 gene of Anabarilius grahami offers molecular insights into the genetic interactions between ancestral carp and Lycoptera and the swift emergence of the expansion of early fish species starting from the early Cretaceous. These findings enhance our understanding of fossil DNA preservation, lay the groundwork for an ancient species DNA database, and introduce innovative tools for exploring evolutionary relationships across geological timescales.

paleontology↗

bioRxiv2023

Integrative Multi-omic Profiling of Two Human Decedents Receiving Pig Heart Xenografts Reveals Strong Perturbations in Early Immune-Cell and Cellular Metabolism Responses.

BackgroundRecent advances in xenotransplantation in living and decedent humans using pig xenografts have laid promising groundwork towards future emergency use and first in human trials. Major obstacles remain though, including a lack of knowledge of the genetic incompatibilities between pig donors and human recipients which may led to harmful immune responses against the xenograft or dysregulation of normal physiology. In 2022 two pig heart xenografts were transplanted into two brain-dead human decedents with a minimized immunosuppression regime, primarily to evaluate onset of hyper-acute antibody mediated rejection and sustained xenograft function over 3 days. MethodsWe performed multi-omic profiling to assess the dynamic interactions between the pig and human genomes in the first two pig heart-xenografts transplants into human decedents. To assess global and specific biological changes that may correlate with immune-related outcomes and xenograft function, we generated transcriptomic, lipidomic, proteomic and metabolomics datasets, across blood and tissue samples collected every 6 hours over the 3-day procedures. ResultsSingle-cell datasets in the 3-day pig xenograft-decedent models show dynamic immune activation processes. We observe specific scRNA-seq, snRNA-seq and geospatial transcriptomic changes of early immune-activation leading to pronounced downstream T-cell activity and hallmarks of early antibody mediated rejection (AbMR) and/or ischemia reperfusion injury (IRI) in the first xenograft recipient. Using longitudinal multiomic integrative analyses from blood in addition to antigen presentation pathway enrichment, we also observe in the first xeno-heart recipient significant cellular metabolism and liver damage pathway changes that correlate with profound physiological dysfunction whereas, these signals are not present in the other xenograft recipient. ConclusionsSingle-cell and multiomics approaches reveal fundamental insights into early molecular immune responses indicative of IRI and/or early AbMR in the first human decedent, which was not evident in the conventional histological evaluations.

systems biology↗

bioRxiv2023

Cholangiocytic differentiation drives cell proliferation in hepatoblastoma through Wnt-dependent FGF19 signaling

Cancers evolve not only through the acquisition and clonal transmission of somatic mutations but also by non-genetic mechanisms that modify cell phenotype. Here, we describe how transcriptional heterogeneity arises within human hepatoblastoma, one of the cancers with the lowest mutational burden, characterized by activating mutations in the Wnt pathway. Histology-guided RNA sequencing and evaluation of spatial gene expression in primary hepatoblastomas identified foci of tumor cells within the highly proliferative embryonal histology that express the growth factor FGF19, colocalizing with markedly increased expression of Wnt target genes and cholangiocyte markers. In patient-derived tumoroids, FGF19 provided a required growth signal for FGF19-negative cells, and its expression depended on both Wnt/-catenin and the biliary transcription factor SOX4. Our results reveal that a biliary lineage program induces FGF19 as a paracrine signal for tumor growth, thereby modulating the transcriptional outcome of constitutive Wnt activation and tumor cell proliferation.

cancer biology↗

bioRxiv2023

Deciphering molecular heterogeneity and dynamics of neural stem cells in human hippocampal development, aging, and injury

While accumulated publications support the existence of neurogenesis in the adult human hippocampus, the homeostasis and developmental potentials of neural stem cells (NSCs) under different contexts remain unclear. Based on our generated single-nucleus atlas of the human hippocampus across neonatal, adult, aging and injury, we dissected the molecular heterogeneity and transcriptional dynamics of human hippocampal NSCs under different contexts. We further identified new specific neurogenic lineage markers that overcome the lack of specificity found in some well-known markers. Based on developmental trajectory and molecular signatures, we found that a subset of NSCs exhibit quiescent properties after birth, and most NSCs become deep quiescence during aging. Furthermore, certain deep quiescent NSCs are re-activated following stroke injury. Together, our findings provide valuable insights into the development, aging, and re-activation of the human hippocampal NSCs, and help to explain why adult hippocampal neurogenesis is infrequently observed in humans.

neuroscience↗

bioRxiv2023

Targeting the catalytic activity of HDAC1 in T cells protects against experimental autoimmune encephalomyelitis

Histone deacetylases are key epigenetic regulators that control T cell-mediated immunity. A T cell-specific deletion of Hdac1 (HDAC1cKO) protects mice against experimental autoimmune encephalomyelitis (EAE). However, it remains elusive whether inhibition of HDAC1 enzymatic activity, which could be achieved therapeutically by HDAC1 inhibitor treatment, is sufficient to block EAE induction. In order to address this question, we generated a novel mouse strain that expresses catalytically inactive HDAC1 (HDAC1Off) from the Rosa26 locus in HDAC1cKO CD4+ T cells to mimic selective inhibition of HDAC1 enzymatic activity in vivo. Mice expressing wildtype HDAC1 in HDAC1cKO CD4+ T cells (HDAC1On) were generated as corresponding controls. In contrast to HDAC1On mice, HDAC1Off mice did not develop EAE, and this correlated with diminished leukocyte CNS infiltration. HDAC1Off CD4+ T cells in the CNS displayed a severe reduction of IFN{gamma}, IL-17A and TNF proinflammatory cytokine expression, and in vivo activated HDAC1Off CD4+ T cells downregulated gene sets associated with T cell activation, cytokine expression and cell migration. This indicates impaired effector functions of HDAC1Off CD4+ T cells. Taken together, our study demonstrates that the inhibition of the catalytic activity of HDAC1 in T cells is sufficient to achieve a clinical benefit in EAE disease development. This raises the translational perspective of pharmacological HDAC1 inhibition for treating human T cell-mediated autoimmune diseases. HighlightsO_LISuccessful generation of a novel mouse model that expresses enzymatic-inactive HDAC1 to mimic HDAC1 inhibitor treatment in vivo. C_LIO_LIMice expressing enzymatically inactive HDAC1 instead of WT HDAC1 in T cells do not develop EAE and display diminished leukocyte CNS infiltration. C_LIO_LIIn vivo activated CD4+ T cells expressing enzymatic inactive HDAC1 downregulate pathways important for T cell activation, cytokine expression and cell migration. C_LIO_LIDemonstrate the proof-of-principle that targeting the enzymatic activity of HDAC1 is a promising treatment strategy for autoimmune diseases. C_LI

immunology↗

bioRxiv2023

Knockdown of Atg1 or Atg18 in adult adipocytes impairs lipophagy and reduces lifespan of fruit flies (Drosophila melanogaster)

Autophagy, a lysosome-based eukaryotic cellular degradation system, has previously been implicated in lifespan regulation in different animal models. In this report, we show that expression of the RNAi transgenes targeting the transcripts of the key autophagy genes such as Atg1 or Atg18 in adult fly muscle or glia does not affect the overall levels of autophagosomes in those tissues and does not change the lifespan of the tested flies, but lifespan reduction phenotype has become apparent when Atg1 RNAi or Atg18 RNAi is expressed in a non-tissue-specific manner through a Tub-Gal4 in adult flies or after lipophagy is eradicated through the knockdown of Atg1 or Atg18 in adult fly adipocytes. Lifespan reduction was also observed when Atg1 or Atg18 was knocked down in adult fly enteroblasts and middle gut stem cells. Over-expression of wildtype Atg1 in adult fly muscle or adipocytes reduces lifespan. High levels of ubiquitinated protein aggregates could be the culprit of the reduced lifespan of Atg1 over-expression flies. Our research data presented here have highlighted the important functions of the key autophagy genes in adult fly adipocytes, enteroblasts, and midgut stem cells for lifespan regulation and their undetermined functions in adult fly muscle and glia. SummaryIn this research, we have demonstrated that the key autophagy genes play important roles in fly lifespan regulation through adult adipose tissues, enteroblasts, and middle gut stem cells.

genetics↗

bioRxiv2023

A brief real-time fNIRS-informed neurofeedback training of the prefrontal cortex changes brain activity and connectivity during subsequent working memory challenge

Working memory (WM) represents a building-block of higher cognitive functions and a wide range of mental disorders are associated with WM impairments. Initial studies have shown that several sessions of functional nearinfrared spectroscopy (fNIRS) informed real-time neurofeedback (NF) allow healthy individuals to volitionally increase activity in the dorsolateral prefrontal cortex (DLPFC), a region critically involved in WM. For the translation to therapeutic or neuroenhancement applications, however, it is critical to assess whether fNIRS-NF success transfers into neural and behavioral WM enhancement in the absence of feedback. We therefore combined single-session fNIRS-NF of the left DLPFC with a randomized sham-controlled design (N = 62 participants) and a subsequent WM challenge with concomitant functional MRI. Over four runs of fNIRS-NF, the left DLPFC NF training group demonstrated enhanced neural activity in this region, reflecting successful acquisition of neural selfregulation. During the subsequent WM challenge, we observed no evidence for performance differences between the training and the sham group. Importantly, however, examination of the fMRI data revealed that - compared to the sham group - the training group exhibited significantly increased regional activity in the bilateral DLPFC and decreased left DLPFC - left anterior insula functional connectivity during the WM challenge. Exploratory analyses revealed a negative association between DLPFC activity and WM reaction times in the NF group. Together, these findings indicate that healthy individuals can learn to volitionally increase left DLPFC activity in a single training session and that the training success translates into WM-related neural activation and connectivity changes in the absence of feedback. This renders fNIRS-NF as a promising and scalable WM intervention approach that could be applied to various mental disorders.

neuroscience↗

bioRxiv2023

Spinal Cord Stimulation using time-dynamic pulses achieves faster and longer reversal of allodynia compared to tonic pulses in a rat model of neuropathic pain

Spinal cord stimulation (SCS) utilizing time-dynamic pulses (TDPs) is an emergent field of neuromodulation that continuously and automatically modulates pulse parameters. We previously demonstrated that TDPs delivered for 60 min at sub-paresthesia amplitudes significantly reversed allodynia in a rat model of neuropathic pain. Because we observed these anti-allodynic effects persisted post-cessation, we investigated the extended temporal dynamics of SCS-induced analgesia. We hypothesized that TDPs achieve a longer duration of analgesia than tonic stimulation. Both TDPs and tonic stimulation reversed PWT to near pre-chronificiation levels within 30 minutes. Most TDPs exhibited significantly slower ramp-up slope (analgesia wash-in rates) compared to tonic stimulation (amplitude modulation: 0.16{+/-}0.03 min-1, pulse width modulation: 0.18{+/-}0.05 min-1, stochastic modulation: 0.17{+/-}0.04 min-1, tonic: 0.31{+/-}0.06 min-1). All TDPs showed slower wind-down slopes (analgesia wash-out rates) compared to tonic (-0.29{+/-}0.07 min-1), with pulse width modulation (-0.11{+/-}0.02 min-1) reaching significance. Extending SCS from 60 to 90 minutes revealed all TDPs maintain analgesic efficacy longer than tonic stimulation, which decreased significantly at both 75 and 90 minutes (from 13.8{+/-}0.5 g to 12.3{+/-}0.9 g and to 11.0{+/-}0.5 g, respectively). Although TDPs and tonic stimulation comparably mitigated allodynia, TDPs generally exhibited slower temporal dynamics, suggesting longer-lasting analgesic effects and potentially different mechanisms of action.

neuroscience↗

bioRxiv2023

CVD-associated SNPs with regulatory potential drive pathologic non-coding RNA expression

BackgroundCardiovascular diseases (CVDs) are the leading cause of death worldwide. Genome-wide association studies (GWAS) have identified many single nucleotide polymorphisms (SNPs) appearing in non-coding genomic regions in CVDs. The SNPs may alter gene expression by modifying transcription factor (TF) binding sites and lead to functional consequences in cardiovascular traits or diseases. To understand the underlying molecular mechanisms, it is crucial to identify which variations are involved and how they affect TF binding. MethodsThe SNEEP (SNP exploration and analysis using epigenomics data) pipeline was used to identify regulatory SNPs, which alter the binding behavior of TFs and link GWAS SNPs to their potential target genes for six CVDs. The human induced pluripotent stem cells derived cardiomyocytes (hiPSC-CMs), monoculture cardiac organoids (MCOs) and self-organized cardiac organoids (SCOs) were used in the study. Gene expression, cardiomyocyte size and cardiac contractility were assessed. ResultsBy using our integrative computational pipeline, we identified 1905 regulatory SNPs in CVD GWAS data. These were associated with hundreds of genes, half of them non-coding RNAs (ncRNAs), suggesting novel CVD genes. We experimentally tested 40 CVD-associated non-coding RNAs, among them RP11-98F14.11, RPL23AP92, IGBP1P1, and CTD-2383I20.1, which were upregulated in hiPSC-CMs, MCOs and SCOs under hypoxic conditions. Further experiments showed that IGBP1P1 depletion rescued expression of hypertrophic marker genes, reduced hypoxia-induced cardiomyocyte size and improved hypoxia-reduced cardiac contractility in hiPSC-CMs and MCOs. ConclusionsIGBP1P1 is a novel ncRNA with key regulatory functions in modulating cardiomyocyte size and cardiac function in our disease models. Our data suggest ncRNA IGBP1P1 as a potential therapeutic target to improve cardiac function in CVDs.

genomics↗

bioRxiv2023

Co-Targeting IL-6 and EGFR signaling for the treatment of schwannomatosis and associated pain

Patients with Schwannomatosis (SWN) overwhelmingly present with intractable, debilitating chronic pain. There are no effective therapies to treat SWN. The drivers of pain response and tumor progression in SWN are not clear. The pain is not proportionally linked to tumor size and is not always relieved by tumor resection, suggesting that mechanisms other than mechanical nerve compression exist to cause pain. SWN research is limited by the lack of clinically-relevant models. Here, we established novel patient-derived xenograft (PDX) models, dorsal root ganglia (DRG) imaging model, and combined with single-cell resolution intravital imaging and RNASeq, we discovered: i) schwannomas on the peripheral nerve cause macrophage influx into the DRG, via secreting HMGB1 to directly stimulate DRG neurons to express CCL2, the key macrophage chemokine, ii) once recruited, macrophages cause pain response via overproduction of IL-6, iii) IL-6 blockade in a therapeutic setting significantly reduces pain but has modest efficacy on tumor growth, iv) EGF signaling is a potential driver of schwannoma growth and escape mechanism from anti-IL6 treatment, and v) combined IL-6 and EGFR blockade simultaneously controlled pain and tumor growth in SWN models. Our findings prompted the initiation of phase II clinical trial (NCT05684692) for pain relief in patients with SWN.

neuroscience↗

bioRxiv2023

Force-regulated spontaneous conformational changes of integrins α5β1 and αVβ3

Force can modulate the properties and functions of macromolecules by inducing conformational changes, such as coiling/uncoiling, zipping/unzipping, and folding/unfolding. Here we compared force-modulated bending/unbending of two purified integrin ectodomains, 5{beta}1 and V{beta}3, using single-molecule approaches. Similar to previously characterized mechano-sensitive macromolecules, the conformation of 5{beta}1 is determined by a threshold head-to-tail tension, suggesting a canonical energy landscape with a deep energy well that traps the integrin in the bent state until sufficient force tilts the energy landscape to accelerate transition to the extended state. By comparison, V{beta}3 exhibits bi-stability even without force and can spontaneously transition between the bent and extended conformations in a wide range of forces without energy supplies. Molecular dynamics simulations revealed consecutive formation and disruption of 7 hydrogen bonds during V{beta}3 bending and unbending, respectively. Accordingly, we constructed an energy landscape with hexa-stable intermediate states to break down the energy barrier separating the bent and extended states into smaller ones, making it possible for the thermal agitation energy to overcome them sequentially and to be accumulated and converted into mechanical work required for V{beta}3 to bend against force. Our study elucidates the different inner workings of 5{beta}1 and V{beta}3 at the sub-molecular level, sheds lights on how their respectively functions are facilitated by their distinctive mechano-sensitivities, helps understand their signal initiation processes, and provides critical concepts and useful design principles for engineering of protein-based biomechanical nanomachines.

biophysics↗

bioRxiv2022

SnapFISH: a computational pipeline to identify chromatin loops from multiplexed DNA FISH data

Multiplexed DNA fluorescence in situ hybridization (FISH) imaging technologies have been developed to map the folding of chromatin fibers at tens of nanometer and tens of kilobase resolution in single cells. However, computational methods to reliably identify chromatin loops from such imaging datasets are still lacking. Here we present a Single-Nucleus Analysis Pipeline for multiplexed DNA FISH (SnapFISH), to process the multiplexed DNA FISH data and identify chromatin loops. SnapFISH can identify known chromatin loops from mouse embryonic stem cells with high sensitivity and accuracy. In addition, SnapFISH obtained comparable results of chromatin loops across datasets generated from diverse imaging technologies.

bioinformatics↗

bioRxiv2022

Rethinking bacterial relationships in light of their molecular abilities

Determining the repertoire of a microbes molecular functions is a central question in microbial biology. Modern techniques achieve this goal by comparing microbial genetic material against reference databases of functionally annotated genes/proteins or known taxonomic markers such as 16S rRNA. Here we describe a novel approach to exploring bacterial functional repertoires without reference databases. Our Fusion scheme establishes functional relationships between bacteria and assigns organisms to Fusion-taxa that differ from otherwise defined taxonomic clades. Three key findings of our work stand out. First, bacterial functional comparisons outperform marker genes in assigning taxonomic clades. Fusion profiles are also better for this task than other functional annotation schemes. Second, Fusion-taxa are robust to addition of novel organisms and are, arguably, able to capture the environment-driven bacterial diversity. Finally, our alignment-free nucleic acid-based Siamese Neural Network model, created using Fusion functions, enables finding shared functionality of very distant, possibly structurally different, microbial homologs. Our work can thus help annotate functional repertoires of bacterial organisms and further guide our understanding of microbial communities.

bioinformatics↗

bioRxiv2022

A comparative atlas of single-cell chromatin accessibility in the human brain

The human brain contains an extraordinarily diverse set of neuronal and glial cell types. Recent advances in single cell transcriptomics have begun to delineate the cellular heterogeneity in different brain regions, but the transcriptional regulatory programs responsible for the identity and function of each brain cell type remain to be defined. Here, we carried out single nucleus ATAC-seq analysis to probe the open chromatin landscape from over 1.1 million cells in 42 brain regions of three neurotypical adult donors. Integrative analysis of the resulting data identified 107 distinct cell types and revealed the cell-type-specific usage of 544,735 candidate cis-regulatory DNA elements (cCREs) in the human genome. Nearly 1/3 of them displayed sequence conservation as well as chromatin accessibility in the mouse brain. On the other hand, nearly 40% cCREs were human specific, with chromatin accessibility associated with species-restricted gene expression. Interestingly, these human specific cCREs were enriched for distinct families of retrotransposable elements, which displayed cell-type-specific chromatin accessibility. We uncovered strong associations between specific brain cell types and neuropsychiatric disorders. We futher developed deep learning models to predict regulatory function of non-coding disease risk variants.

neuroscience↗

bioRxiv2022

A ZTF-7/RPS-2 complex mediates the cold-warm response in C. elegans

Temperature greatly affects numerous biological processes in all organisms. How multicellular organisms respond to and are impacted by hypothermic stress remains elusive. Here, we found that cold-warm stimuli induced depletion of the RNA exosome complex in the nucleoli but enriched it in the nucleoplasm. To further understand the function and mechanism of cold-warm stimuli, we conducted forward genetic screening and identified ZTF-7, which is required for RNA exosome depletion from nucleoli upon transient cold-warm exposure in C. elegans. ZTF-7 is a putative ortholog of human ZNF277 that may contribute to language impairments. Immunoprecipitation followed by mass spectrometry (IP-MS) found that ZTF-7 interacted with RPS-2, which is a ribosomal protein of the small subunit and participates in pre-rRNA processing. A partial depletion of RPS-2 and other proteins of the small ribosomal subunit blocked the cold-warm stimuli-induced reduction of exosome subunits from the nucleoli. These results established a novel mechanism by which C. elegans responds to environmental cold-warm exposure.

genetics↗

bioRxiv2022

Targeting the pathological network: feasibility of network-based optimization of transcranial magnetic stimulation coil placement for treatment of psychiatric disorders

It has been recognized that the efficacy of TMS-based modulation may depend on the network profile of the stimulated regions throughout the brain. However, what profile of this stimulation network optimally benefits treatment outcomes is yet to be addressed. The answer to the question is crucial for informing network-based optimization of stimulation parameters, such as coil placement, in TMS treatments. In this study, we aimed to investigate the feasibility of taking a disease-specific network as the target of stimulation network for guiding individualized coil placement in TMS treatments. We present here a novel network-based model for TMS targeting of the pathological network. First, combining E-field modeling and resting-state functional connectivity, stimulation networks were modeled from locations and orientations of the TMS coil. Second, the spatial anti-correlation between the stimulation network and the pathological network of a given disease was hypothesized to predict the treatment outcome. The proposed model was validated to predict treatment efficacy from the position and orientation of TMS coils in two depression cohorts and one auditory verbal hallucinations cohort. We further demonstrate the utility of the proposed model in guiding individualized TMS treatment for psychiatric disorders. In this proof-of-concept study, we demonstrated the feasibility of the novel network-based targeting strategy that uses the whole-brain, system-level abnormity of a specific psychiatric disease as a target. Results based on empirical data suggest that the strategy may potentially be utilized to identify individualized coil parameters for maximal therapeutic effects. HighlightsO_LIProposed a model of targeting pathological brain networks for pre-treatment TMS coil placement planning in the treatment of psychiatric disorders; C_LIO_LIValidated the network targeting model in three cohorts of patients with depression or auditory verbal hallucinations, via prediction of individual TMS treatment efficacy from the parameters of coil placement; C_LIO_LIDemonstrated the utility of the network targeting model in guiding individualized TMS coil placement. C_LI

neuroscience↗

bioRxiv2022

Recognition of Galactose by a Scaffold Protein Recruits a Transcriptional Activator for the GAL Regulon Induction in Candida albicans

The GAL pathway of yeasts has long served as a model system for understanding of how regulatory mode of eukaryotic metabolic pathways evolves. While Gal4 mode has been well-characterized in Saccharomycetaceae clade, little is known about the regulation of the GAL pathway in other yeasts. Here, we find that Rep1, a Ndt80-like family transcription factor, serves as a galactose sensor in the commensal-pathogenic fungus Candida albicans. It is presented at the GAL gene promoters independent of the presence of galactose. Rep1 recognizes galactose via a direct physical interaction. The net result of this interaction is the recruitment of a transcriptional activator Cga1 (Candida galactose gene activator, orf19.4959) and transcription of the GAL genes proceeds. Rep1 and Cga1 are conserved across the CTG species. Rep1 itself does not possess transcriptional activity. Instead, it provides a scaffold to recruit different factors for transcriptional regulation. Rep1-Cga1 mode of regulation represents a new example of network rewiring in fungi, which provides insight into how C. albicans evolves transcriptional programs to colonize diverse host niches.

molecular biology↗