Biology subjects

Tanaka, Y.

Publications and source records attributed to Tanaka, Y..

At least 55 records · Page 3Linked to original sources

bioRxiv2025

Non-DNA-damaging DNA-PK activation improving hearing and prolonging life due to NAD+ and SIRT upregulation

Emerging evidence strongly supports a close relationship between age-related hearing loss and frailty, highlighting the importance of early detection and intervention. Recently, we invented a mitochondria-homing drug named mitochonic acid 5 (MA-5), that increases the adenosine triphosphate (ATP) levels, rescue mitochondrial function, and protect tissue damages. Currently, the phase I clinical trial has been finished in Japan (jRCT2031210495) and the phase 2 clinical trial has already been approved by PMDA. Here we show that MA-5 improved various types of hearing loss in mouse models. Structural chemical bioanalysis revealed that MA-5 is a mixture of equal amount of S- and R- enantiomer and both S- and R- enantiomer increase ATP by binding mitochondrial protein, mitofilin. However, S-enantiomer significantly increased the NAD+ levels by binding to the NAD+-producing key enzyme nicotinamide phosphoribosyltransferase (NAMPT). Moreover, the S-enantiomer increased the sirtuin 1 protein by suppressing polyubiquitination induced by tripartite motif containing 28 (TRIM28) phosphorylation which was triggered by DNA-dependent protein kinase (DNA-PK) activation in the absence of DNA damage. Transcriptomic signatures showed that the signature of MA-5 shows an inverse correlation with aging and mortality and is oriented in the same direction as the OSKM-related iPSCs, suggesting the modification of aging pathways. Oral administration of MA-5 to mitochondrial disease model mouse showed increased survival. Our findings suggest that, in addition to enhancing ATP levels, the coordinated regulation of NAD+ metabolism, SIRT protein expression, and DNA-PK activity-constituting a novel therapeutic triad may contribute to the amelioration of hearing impairment and mitochondrial dysfunction, thereby improving life prognosis.

cell biology↗

bioRxiv2025

Compositional selection of phospholipid compartments in icy environments drives the inheritance of encapsulated genetic information

The lipid world hypothesis proposes that both intracellular components and the chemical composition of the membrane compartment carry heritable information that contributes to protocellular fitness. However, there are few experimental demonstrations of membrane compositional selection and no study has shown that phospholipids--the primary membrane components of modern cells--can support selection of this type. As lipid compartments generally grow in size before fission, faster-growing compartments should enjoy a selective advantage that favors both the membrane itself and the contents it hosts. When situated in icy environments undergoing cycles of freezing and thawing (F/T), we found that the growth of phospholipid vesicles depends on their phospholipid composition: Vesicles with more unsaturated bonds in the acyl chain showed higher growth efficiency. When vesicles composed of lipids with either one or two unsaturated bonds were mixed and subjected to F/T cycles, a selective enrichment of the lipid with two unsaturated bonds was observed. Moreover, selection acting on lipid composition was propagated to the encapsulated genetic material, which was also enriched while selectively neutral. We conclude that phospholipid composition can be a direct target of selection for grown vesicles under an icy environment leading to indirect but concurrent enrichment of compartmentalized genetic molecules.

synthetic biology↗

bioRxiv2025

Simultaneous knockout of VITAMIN C DEFECTIVE 2 and 3 exacerbates ascorbate deficiency and light stress sensitivity

Light-dependent activation of ascorbate biosynthesis is essential for accumulating ascorbate to mitigate photooxidative stress. The VTC2 and VTC3 genes play key roles in this process: VTC2 encodes GDP-L-galactose phosphorylase (GGP), the rate-limiting enzyme in ascorbate biosynthesis, and VTC3 encodes a putative protein kinase/phosphatase with an unknown function. Here, we investigated their functional and genetic relationship. In vtc3 mutants, VTC2 transcription and GGP activity were slightly enhanced, suggesting that VTC3 is not required for VTC2 expression. Additionally, the vtc3 mutation had negligible effects on the transcriptome and the activity of enzymes involved in ascorbate redox cycle regulation, narrowing down the possible roles of VTC3 in ascorbate biosynthesis. Under low-light conditions, ascorbate levels were lower in vtc2 than in vtc3 mutants, but vtc2 retained the ability to increase ascorbate levels under high-light stress, unlike vtc3. The simultaneous knockout of VTC2 and VTC3 further reduced ascorbate levels compared to single mutants and severely impaired light stress-induced ascorbate accumulation, resulting in impaired non-photochemical quenching and enhanced photooxidative damage. These findings highlight the additive effects of VTC2 and VTC3 on ascorbate biosynthesis and stress tolerance. The vtc2 vtc3 double mutants provide a valuable model for further elucidating the physiological roles of ascorbate in plants.

plant biology↗

bioRxiv2025

Structural basis of a phosphotransferase system xylose transporter

The bacterial phosphotransferase system (PTS) is essential for carbohydrate uptake, and IIC transporters in the system facilitate intracellular sugar transport. Here, we report the crystal and cryo-EM structures of Leminorella grimontii GatC (LgGatC), a putative xylose transporter in the IIC family, in its outward-facing state. Structural analysis indicates that the outward-facing cavity recognizes the linear form of D-xylose. A structure-based homology model of an inward-facing state supports an elevator-like sugar transport mechanism. These findings provide insights into PTS-mediated xylose transport and its potential applications in microbial engineering.

molecular biology↗

bioRxiv2025

Rapid pronucleus assembly using cytoplasmic RNAs in fertilized eggs of Xenopus laevis

The size of the nucleus, which serves as the site for essential cellular functions such as replication and transcription, is dynamically altered to support these functions in response to the surrounding environment. During the brief cleavage period in metazoan embryos, the small, hypercondensed sperm nucleus with silenced chromatin undergoes a dramatic transformation into a large, round pronucleus with relaxed chromatin, enabling the activation of chromatin functions necessary for subsequent development. However, it remains unclear whether the egg cytoplasm-specific molecular environment plays a role in pronucleus assembly. In this study, we evaluated the impact of abundant RNAs in eggs on pronucleus assembly by utilizing a cell-free reconstruction of interphase nuclei in Xenopus laevis egg extract. We found that when RNA levels deviated from the conventional concentration, the growth rate of the interphase nucleus decreased. Additionally, the addition of RNAs led to a more dispersed chromatin distribution and the dissociation of sperm-specific nuclear proteins from the chromatin. These chromatin remodeling properties, which were reproducible with the introduction of cationic compounds, facilitated the incorporation of somatic histones into the chromatin in reconstructed nuclei. Based on these findings, we propose that cytoplasmic RNAs promote the rapid decondensation of negatively charged chromatin from a hypercompacted state and the removal of positively charged protamines from sperm chromatin via electrical interactions. This remodeling accelerates pronucleus assembly during the brief cleavage period following fertilization and promotes the rapid growth in nucleus size.

developmental biology↗

bioRxiv2025

Hematopoietic stem cells undergo bidirectional fate transitions in vivo.

Differentiation of haematopoietic stem and progenitor cells (HSPCs) is widely considered unidirectional in vivo. Here, we developed clonal phylogenetic tracing (CP-tracer) by sequential genetic barcoding, which enabled high-resolution analysis of 181,695 subclones derived from 847 individually labelled HSPCs. This approach uncovered bidirectional fate transitions between myeloid-biased (My-) and lineage-balanced haematopoietic stem cells (HSCs). Individual HSC clones, distinguished by temporally unique serial barcodes, exhibited durable lineage bidirectionality, with dynamics favouring progressive accumulation of My-HSCs over time. CRISPR-Cas9 screening identified the homeobox gene Hhex as a suppressor of myeloid differentiation that enables pivoting toward balanced output. Hhex function is age-dependent, with its expression declining in aged HSCs. Together, these findings demonstrate unexpected plasticity in HSC differentiation, modulated in part by Hhex-mediated repression, that shifts over time to drive the myeloid bias characteristic of ageing.

cell biology↗

bioRxiv2024

Integrated hepatic ferroptosis gene signature dictates pathogenic features of ferroptosis

Background & AimsFerroptosis, a distinctive form of cell death induced by iron-dependent lipid peroxidation, is implicated in various biological processes, including liver diseases. Establishing an iron overload-induced ferroptosis model and identifying hepatic gene signatures associated with ferroptosis are crucial for understanding its role in liver pathogenesis. MethodsF-box and leucine-rich repeat protein 5 (FBXL5) is a substrate-recognition component of the SCF E3 ligase complex that restricts intracellular iron levels. In this study, we used liver-specific Fbxl5-null mice to establish an iron overload-induced ferroptosis model. Transcriptome analysis identified genes involved in hepatic ferroptosis. Integrating these gene signatures with another ferroptosis model enabled the assessment of ferroptosis-related pathology in murine liver injury models and in 174 patients undergoing liver resection surgery. ResultsIron overload induced severe liver damage in liver-specific Fbxl5-null mice, characterized by elevated liver enzymes, histopathological changes, and lipid peroxidation. Transcriptome analysis revealed a distinct set of genes associated with hepatic ferroptosis response. Generating a gene signature for evaluating ferroptosis enhanced the understanding of ferroptosis-related pathologies in liver diseases. Iron overload exacerbated liver damage in murine ischemia-reperfusion injury models via ferroptosis induction. In human patients, elevated serum iron levels correlated with sustained post-operative liver damage, indicating heightened susceptibility to ferroptosis. ConclusionHere, a murine model of iron overload-induced hepatic ferroptosis was established, and a gene signature indicative of hepatic ferroptosis response in both mice and humans was identified. These findings underscore the role of ferroptosis in liver injury progression and suggest potential therapeutic targets for liver disease intervention. HIGHLIGHTSO_LILiver-specific Fbxl5 knockout mice provide an iron-induced ferroptotic injury model C_LIO_LIIntegrated gene signature of iron- and acetaminophen-induced liver injury dictates ferroptosis C_LIO_LIIron overload aggravates hepatic ischemia-reperfusion injury in mice C_LIO_LIPatients with high iron levels show delayed post-operative liver damage recovery C_LI IMPACT AND IMPLICATIONSOur study elucidated the critical role of iron in liver disease pathogenesis and ischemia-reperfusion injury (IRI). By establishing a murine model of iron overload-induced ferroptosis, we confirmed that iron overload exacerbated hepatic IRI, underscoring the importance of ferroptosis in liver damage. Additionally, the development of an integrated gene signature for hepatic ferroptosis response provides a valuable tool for evaluating ferroptosis in liver diseases. Via analysis of patient data, we also highlighted the clinical relevance of ferroptosis in post-operative liver damage, offering insights into potential therapeutic strategies targeting iron and ferroptosis to improve outcomes in patients with liver diseases.

molecular biology↗

bioRxiv2024

Brain-Body Interactions Influence the Transition from Mind Wandering to Awareness of Ongoing Thought

Our thoughts are inherently dynamic and often wander far from our current situation (mind wandering, MW). Although previous research revealed that the ascending arousal system shapes neural dynamics to mediate awareness of ongoing thoughts, the physiological states and afferent signals altered by this activation and its effects on awareness are unknown. In this study, we examined electroencephalography (EEG), electrocardiography (ECG), and respiration data before participants were aware of MW during a task in which they focused on external or internal stimuli. We showed that the transition from MW to awareness was characterized by decreased alpha and beta activity and increased heartbeat-evoked potential (HEP) amplitudes. In addition, the participants were more likely to be in the exhalation phase becoming aware, and in the inhalation phase at the time of MW reports. Moreover, changes in cardiac activity and HEP accompanied this pattern when participants were asked to focus on respiration. Based on these findings, we suggest that the release from the increased cognitive load with sustained MW and catching these changes as physiological alterations supporting awareness of MW; moreover, the modulation of the respiratory cycle by focusing on breathing enhances these changes.

neuroscience↗

bioRxiv2024

Evaluating Methods for the Prediction of Cell Type-Specific Enhancers in the Mammalian Cortex

Identifying cell type-specific enhancers in the brain is critical to building genetic tools for investigating the mammalian brain. Computational methods for functional enhancer prediction have been proposed and validated in the fruit fly and not yet the mammalian brain. We organized the Brain Initiative Cell Census Network (BICCN) Challenge: Predicting Functional Cell Type-Specific Enhancers from Cross-Species Multi-Omics to assess machine learning and feature-based methods designed to nominate enhancer DNA sequences to target cell types in the mouse cortex. Methods were evaluated based on in vivo validation data from hundreds of cortical cell type-specific enhancers that were previously packaged into individual AAV vectors and retro-orbitally injected into mice. We find that open chromatin was a key predictor of functional enhancers, and sequence models improved prediction of non-functional enhancers that can be deprioritized as opposed to pursued for in vivo testing. Sequence models also identified cell type-specific transcription factor codes that can guide designs of in silico enhancers. This community challenge establishes a benchmark for enhancer prioritization algorithms and reveals computational approaches and molecular information that are crucial for identifying functional enhancers in mammalian cortical cell types. The results of this challenge bring us closer to understanding the complex gene regulatory landscape of the mammalian cortex and to designing more efficient genetic tools to target cortical cell types.

genomics↗

bioRxiv2024

CH-related Mutant ASXL1 Promotes Atherosclerosis in Mice via Dysregulated Innate Immunity

Certain somatic mutations confer a fitness advantage in hematopoietic stem and progenitor cells (HSPCs) over normal HSPCs, resulting in the clonal expansion of mutant blood cells1, otherwise known as clonal haematopoiesis (CH). CH is frequently observed among healthy elderly people and is closely associated with the risk of cardiovascular diseases (CVDs). The most frequently mutated genes of CH include DNMT3A, TET2, and ASXL12. Among them, even though ASXL1 mutations are clinically associated with the highest risk for developing CVDs, little is known whether and how the mutations contribute to CVDs. Here we show accelerated development of atherosclerosis and increased inflammatory monocytes in mice transplanted with the bone marrow cells (BMCs) from the mice expressing mutant ASXL1 (ASXL1-MT) selectively in hematopoietic cells. RNA sequencing analysis of the plaque-macrophages derived from BMCs expressing ASXL1-MT showed more inflammatory signatures than those from control BMCs. Mechanistically, wild-type ASXL1 inhibited innate immune signalling through direct interactions with IRAK1/TRAF6/TAK1 in the cytoplasm, while ASXL1-MT, which only interacted with TAK1, lost this regulatory function, leading to NF-{kappa}B activation. This mechanism is unique and distinct from those of CH with Tet2 or Dnmt3a mutations, where overactivation of the IL-1{beta}/NLRP3 inflammasome plays critical roles3-5. Intriguingly, IRAK1/4 inhibition decreased the number of inflammatory monocytes and attenuated the development of atherosclerosis driven by ASXL1-MT. The present work connects the mutations of an epigenetic factor, ASXL1, with inflammation and CVDs and gives an indication for the prevention of CVDs in CH.

cell biology↗

bioRxiv2024

Effects of unconscious tactile stimuli on autonomic nervous activity and afferent signal processing

Autonomic nervous system (ANS) is a mechanism that regulates our internal environment. In recent years, the interest in how tactile stimuli presented directly to the body affect ANS function and cortical processing in humans has been renewed. However, it is not yet clear how subtle tactile stimuli below the level of consciousness affect human heart rate and cortical processing. To examine this, subthreshold electrical stimuli were presented to the left forearm of 43 participants during an image-viewing task, and electrocardiogram (ECG) and electroencephalogram (EEG) data were collected. The changes in the R-wave interval of the ECG immediately after the subthreshold electrical presentation and heartbeat-evoked potential (HEP), the afferent signal processing of cardiac activity, were measured. The results showed that heart rate decelerated immediately after the presentation of subthreshold electrical stimuli. The HEP during stimulus presentation was amplified for participants with greater heart rate acceleration immediately after this deceleration. The magnitude of these effects depended on the type of the subthreshold tactile stimuli. The results suggest that even with subthreshold stimulation, the changes in autonomic activity associated with orienting response and related afferent signal processing differ depending on the clarity of the tactile stimuli.

neuroscience↗

bioRxiv2024

Kinesin-1 mediates proper ER folding of the CaV1.2 channel and maintains mouse glucose homeostasis

Glucose-stimulated insulin secretion (GSIS) from pancreatic beta cells is a principal mechanism for systemic glucose homeostasis, of which regulatory mechanisms are still unclear. Here we show that kinesin molecular motor KIF5B is essential for GSIS through maintaining the voltage-gated calcium channel CaV1.2 levels, by facilitating an Hsp70-to-Hsp90 chaperone exchange to pass through the quality control in the endoplasmic reticulum (ER). Phenotypic analyses of KIF5B conditional knockout (cKO) mouse beta cells revealed significant abolishment of glucose-stimulated calcium transients, which altered the behaviors of insulin granules via abnormally stabilized cortical F-actin. KIF5B and Hsp90 colocalize to microdroplets on ER sheets, where CaV1.2 but not Kir6.2 is accumulated. In the absence of KIF5B, CaV1.2 fails to be transferred from Hsp70 to Hsp90 and is likely degraded via the proteasomal pathway. KIF5B and Hsc70 overexpression increased CaV1.2 expression via enhancing its chaperone binding. Thus, ER sheets may serve as the place of KIF5B- and Hsp90-dependent chaperone exchange, which predominantly facilitates CaV1.2 production in beta cells and properly enterprises GSIS against diabetes.

cell biology↗

bioRxiv2024

Antifungal potency of terbinafine as a therapeutic agent against Exophiala dermatitidis in vitro

SynopsisO_ST_ABSBackgroundC_ST_ABSExophiala dermatitidis (E. dermatitidis), which causes skin infections or respiratory diseases, is occasionally fatal in immunocompromised patients. ObjectivesHere, we report the unique antifungal potency of terbinafine (TRB), which targets squalene epoxidase, against E. dermatitidis (SQLEED) using various in vitro approaches. MethodsBased on the human SQLE crystal structure, we created a structure model of SQLEED using SWISS-MODEL and determined the best-fitting model of TRB to the SQLEED. The versatile antifungal activities, including fungicidal activity, biofilm inhibition, biofilm eradication activity, and the combination effect of TRB, posaconazole (PSC), and amphotericin B (AmB) with great antifungal potency against E. dermatitidis were evaluated using crystal violet and cell viability assay. ResultsClinically isolated E. dermatitidis increased most vigorously at 30{degrees}C but decreased at 40{degrees}C. E. dermatitidis hyphae elongated and attached to a cell scaffold, forming a membrane-like biofilm that was distinct from the cell-free biofilm. In the binding model, TRB formed an H-bond with Y102 and was surrounded by key amino acid residues of SQLEED corresponding to TRB-resistant mutations in Trichophyton rubrum, showing an appropriate interaction. Among TRB, PSC, and AmB with potent antifungal activities, TRB and PSC showed more potent antibiofilm activities than AmB. In addition, TRB and PSC exhibited residual potency without incubation against E. dermatitidis, decreasing the growth at lower concentrations than AmB. In contrast, AmB exhibited strong time-dependent killing and eradication activities. The combination of TRB and PSC was more effective than that of TRB and AmB or PSC and AmB in vitro. ConclusionsAlthough the tissue migration of TRB must be considered, these data suggest that TRB and PSC may be useful agents and a potent combination in severely immunocompromised patients with refractory and systemic E. dermatitidis infection.

microbiology↗

bioRxiv2024

The Rubicon-WIPI axis regulates exosome biogenesis during aging

Cells release intraluminal vesicles (ILVs) in multivesicular bodies as exosomes to communicate with other cells. Although recent studies suggest an intimate link between exosome biogenesis and autophagy, the detailed mechanism is not fully understood. Here we employed comprehensive RNAi screening for autophagy-related factors and discovered that Rubicon, a negative regulator of autophagy, is essential for exosome release. Rubicon recruits WIPI2d to endosomes to promote exosome biogenesis. Interactome analysis of WIPI2d identified the ESCRT components that are required for ILV formation. Notably, we found that Rubicon is required for an age-dependent increase of exosome release in mice. In addition, small RNA sequencing of serum exosomes revealed that Rubicon determines the fate of exosomal microRNAs associated with cellular senescence and longevity pathways. Taken together, our current results suggest that the Rubicon-WIPI axis functions as a key regulator of exosome biogenesis and is responsible for the age-dependent changes in exosome quantity and quality.

cell biology↗

bioRxiv2024

A heterocyclic compound inhibits viral release by inducing cell surface BST2/Tetherin/CD317/HM1.24

The introduction of combined antiretroviral therapy (cART) has greatly improved the quality of life of human immunodeficiency virus type 1 (HIV-1)-infected individuals. Nonetheless, the ever-present desire to seek out a full remedy for HIV-1 infections makes the discovery of novel antiviral medication compelling. Owing to this, a new late-stage inhibitor, Lenacapavir/Sunlenca, an HIV multi-phase suppressor, was clinically authorized in 2022. Besides unveiling cutting-edge antivirals inhibiting late-stage proteins or processes, newer therapeutics targeting host restriction factors hold promise for the curative care of HIV-1 infections. Notwithstanding, bone marrow stromal antigen 2 (BST2)/Tetherin/CD317/HM1.24, which entraps progeny virions is an appealing HIV-1 therapeutic candidate. In this study, a novel drug screening system was established, using the Jurkat/Vpr-HiBiT T cells, to identify drugs that could obstruct HIV-1 release; the candidate compounds were selected from the Ono Pharmaceutical compound library. Jurkat T cells expressing Vpr-HiBiT were infected with NL4-3, and the amount of virus release was quantified indirectly by the amount of Vpr-HiBiT incorporated into the progeny virions. Subsequently, the candidate compounds that suppressed viral release were used to synthesize the heterocyclic compound, HT-7, which reduces HIV-1 release with less cellular toxicity. Notably, HT-7 increased cell surface BST2 coupled with HIV-1 release reduction in Jurkat cells but not Jurkat/KO-BST2 cells. Seemingly, HT-7 impeded simian immunodeficiency virus (SIV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) release. Concisely, these results suggest that the reduction in viral release, following HT-7 treatment, resulted from the modulation of cell surface expression of BST2 by HT-7. ImportanceA collection of scientific strategies has been revealed to find long-term cure for HIV-1 infection. One of these techniques, the therapeutic approach, involves harnessing late events that are not targeted by current medication. The regulator of HIV-1 assembly and release, the HIV-1 Gag protein, has emerged as a prospective inhibitor. We set up a high-efficiency, economically viable, and facile screening system for the identification of late-stage inhibitors. Herein, we discovered a heterocyclic compound that inhibits HIV-1 release. This newly high- performance testing technique can be employed in virological research for investigating HIV- 1 late-stage processes.

microbiology↗

bioRxiv2024

Structural basis for bispecific antibody design: arrangement of domain linkage produces activity enhancement

A bispecific antibody (BsAb) is a protein genetically engineered from two different antibodies, allowing simultaneous binding to two kinds of antigen to bring them into close proximity. BsAbs have been developed as anti-cancer drugs that accumulate lymphocytes onto cancer cells by bridging antigens present on each. Ex3 is a bispecific diabody composed of the two fused variable regions (Fvs) of an anti-epidermal growth factor receptor (EGFR) antibody and an anti-CD3 antibody with potent cancer cytotoxic activity. In Ex3, the LH-type, in which the variable regions of the light chain (VLs) are located at the N-terminus of those of the heavy chain (VHs), exerted 1000-fold greater anticancer activity than the HL-type, in which the VHs are located at the N-terminus of the VLs. This effect (termed activity enhancement), in which the activity is greatly enhanced by domain rearrangement, has been reported not only for Ex3 but also for several other BsAbs. However, the molecular details of this activity enhancement have yet to be elucidated. In this study, we determined the cryo-EM structures of Ex3 LH- and HL-types in complex with CD3 and EGFR. Structural comparison of the LH- and HL-types showed that rearrangement of the domain linkage produces drastic structural differences in the overall shape of these complexes, and dynamics attributed to the flexibility between the two Fvs. These findings provide valuable insights into the molecular mechanism for the activity enhancement of BsAbs. This study will be a stepping stone towards establishing a design foundation for BsAb development.

biochemistry↗

bioRxiv2024

FOXA1 is required for ErbB2 expression and luminal differentiation in HER2-positive breast cancer

The function of the pioneer factor forkhead box A1 (FOXA1) in estrogen receptor (ER)-negative, human epidermal growth factor receptor 2 (HER2, encoded by the ERBB2 gene)-positive breast cancer represents a critical gap in our understanding of lineage identity in tumorigenesis. Here, we solve this enigma by addressing this question through the identification of an indispensable, co-dependent regulatory circuit formed between FOXA1 and the SAM pointed domain containing ETS-family transcription factor (SPDEF). Using integrative multi-omics analyses of patient tumors and experimental models, we demonstrate that this circuit functions as the master guardian of the HER2-positive luminal state. It executes this role via two distinct, essential mechanisms: it directly binds regulatory elements to drive high-level expression of the ERBB2 oncogene, and it simultaneously preserves epithelial identity by suppressing a latent program of epithelial-to-mesenchymal transition (EMT). Mechanistically, the FOXA1/SPDEF circuit promotes the expression of the transcriptional repressor TRPS1, which in turn antagonizes the pro-mesenchymal activity of the TEAD/YAP complex. Our findings define a central regulatory node that couples lineage fidelity to oncogenic output in HER2-positive cancer, revealing the FOXA1/SPDEF-TRPS1 axis as a critical determinant of tumor plasticity and a potential therapeutic target for overcoming resistance in HER2-positive breast cancer.

cancer biology↗

bioRxiv2024

DERIVATION OF ELEPHANT INDUCED PLURIPOTENT STEM CELLS

The crisis of biodiversity loss in the anthropogenic era requires new tools for studying non-model organisms. Elephants, for example, are both an endangered species and excellent models studying complex phenotypes like size, social behavior, and longevity, but they remain severely understudied. Here we report the first derivation of elephant (Elephas maximus) induced pluripotent stem cells (emiPSCs) achieved via a two-step process of chemical-media induction and colony selection, followed by overexpression of elephant transcription factors OCT4, SOX2, KLF4, MYC {+/-} NANOG and LIN28A, and modulation of the TP53 pathway. Since the seminal discovery of reprogramming by Shinya Yamanaka, iPSCs from many species including the functionally extinct northern white rhinocerous have been reported, but emiPSCs have remained elusive. While for multiple species the reprogramming protocol was adopted with little changes compared to model organisms like mouse and human, our emiPSC protocol requires a longer timeline and inhibition of TP53 expansion genes that are hypothesized to confer unique cancer resistance in elephants. iPSCs unlock tremendous potential to explore cell fate determination, cell and tissue development, cell therapies, drug screening, disease modeling, cancer development, gametogenesis and beyond to further our understanding of this iconic megafauna. This study opens new frontiers in advanced non-model organism cellular models for genetic rescue and conservation.

cell biology↗