Biology subjects

Davis, A.

Publications and source records attributed to Davis, A..

At least 19 recordsLinked to original sources

bioRxiv2026

Phenotypic screening in Parkinson's iPSC-dopamine neurons identifies the FASN-SREBP1 axis as a potential therapeutic target

Parkinson's disease (PD) remains highly challenging to model in vitro, particularly when seeking robust functional phenotypes for target discovery. Patient-derived induced pluripotent stem cell dopaminergic neurons (iPSC-DANs) offer a promising platform to address this challenge. Because calcium dyshomeostasis is well-described in PD pathophysiology, it offers a platform for phenotypic screening. We have previously shown that GBA-N370S iPSC-DANs display impaired intracellular calcium release. Here, we used this disease-relevant phenotype to undertake a 4,108-compound phenotypic screen in GBA-N370S (GBA-NS) iPSC-DANs. This screen identified fatty acid synthase (FASN) as the most enriched protein target. The ability of compounds to rescue calcium release correlated with biochemical potency against FASN across multiple chemical series. We confirmed that FASN knockdown increased intracellular calcium release, supporting an on-target effect. Untargeted lipidomics demonstrated broad remodelling of the neuronal lipidome after FASN inhibition, confirming target engagement. FASN inhibition also increased active a-glucocerebrosidase (GCase), reduced extracellular a-synuclein release and ER stress, and altered RASGRF1 expression. Mechanistically, FASN inhibition activated sterol regulatory element-binding protein 1 (SREBP1), and SREBP1 overexpression alone was sufficient to increase intracellular calcium release, identifying a FASN-SREBP1-calcium homeostasis axis in human neurons. Finally, the FASN inhibitor BI 99179 achieved brain exposure and reduced brain fatty acid levels while inducing an SRE-associated transcriptional response in a Parkinson's mouse model, providing evidence of in vivo target engagement. These findings establish patient iPSC-neuron functional screening as a tractable discovery platform to identify targets which can be taken in vivo and nominate the FASN-SREBP1 axis as a candidate therapeutic pathway in PD.

neuroscience↗

bioRxiv2026

MTHFR*677C>T produces distinct prodromal disease signatures in a mouse model of late-onset Alzheimer's disease

Background: Late-onset Alzheimer's disease (LOAD) comprises more than 95% of all AD cases. Transgenic, overexpression animal models have off target side effects, do not effectively produce the heterogeneity observed clinically in LOAD patients, and are therefore not best suited for preclinical therapeutic development. The Model Organism Development and Evaluation for Late-onset Alzheimer's Disease (MODEL-AD) Consortium was established to develop novel mouse strains to model human-relevant genetic and environmental risk factors for LOAD. Methylenetetrahydrofolate reductase (MTHFR) is an enzyme in the folate/methionine pathway. Variants in the MTHFR gene, notably 677C>T, are associated with ADRD, and we have previously shown the Mthfr677C>T mouse model phenocopies humans carrying the variant and develop cerebrovascular deficits. Methods: To examine the contributions of Mthfr677C>T in the context of late-onset Alzheimer's disease (LOAD), MODEL-AD created a novel mouse strain on the C57BL/6J (B6) background that was homozygous for Mthfr677C>T, in combination with humanized Abeta;, APOEe4, and Trem2*R47H (referred to as LOAD2.Mthfr677C>T). Mice were assessed over multiple ages for disease-relevant phenotypes. Regular behavior measurements and biometric samples were collected longitudinally to 24 months of age. Blood and brain tissue were collected for transcriptomics, proteomics, human disease correlation, and neuropathology. Results: Despite lacking hallmark pathologies such as amyloid deposition and significant neuroinflammation, compared to LOAD2 controls, LOAD2.Mthfr677C>T mice showed transcriptional and proteomic signatures in the brain that relate to the cerebrovasculature, myelination, and synaptic biology, similar to those seen in human LOAD patients. Conclusions: These data further support the use of the LOAD2.Mthfr677C>T mouse model to study aspects of ADRD such as cerebrovascular compromise.

neuroscience↗

bioRxiv2026

NAMPT activation uncovers a senescence-specific vulnerability and promotes healthy aging in combination with NAM

Aging is driven by multiple interacting processes, suggesting that effective strategies to promote healthy aging may require simultaneous targeting of more than one underlying mechanism. Here we identify a strategy that couples restoration of nicotinamide adenine dinucleotide (NAD+) homeostasis with selective targeting of senescent cells, two mechanistically linked features of aging. Senescent cells express elevated intracellular levels of nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in the nicotinamide (NAM) salvage pathway for NAD+ biosynthesis. Despite increased NAMPT abundance, isotope-tracing studies revealed decreased NAD+ biosynthesis and consumption, indicating that elevated NAMPT abundance was not accompanied by a corresponding increase in NAD+ metabolic flux. Treatment with the NAMPT activator SBI-0802162 engaged the spare enzymatic capacity of NAMPT in senescent cells and produced a marked rise in intracellular NAD+ that, when sustained, disrupted their transcriptional program and selectively reduced the viability of senescent cells but not proliferating cells. In mice, SBI-0802162 reduced circulating NAM levels, suggesting that sustained NAMPT activation may be limited by substrate availability. This observation prompted the development of a combination approach using SBI-0802162 together with dietary NAM supplementation. Co-administration of SBI-0802162 and NAM robustly increased tissue NAD+, suppressed select age-associated inflammatory signatures and markers of cellular senescence in a tissue-specific manner. These molecular effects occurred alongside preserved physical performance in aged mice and reductions in food intake and body weight, which were observed whether SBI-0802162 was present in the chow or administered by oral gavage. Together, these findings establish a mechanistically integrated approach to target two convergent features of aging, NAD+ dysregulation and senescent cell accumulation, and support combined NAMPT activation and NAM supplementation as a strategy to promote healthy aging.

molecular biology↗

bioRxiv2026

Ultramutagenesis through combined Msh2 depletion and proofreading-deficient DNA polymerase ε expression enhances small molecule target identification in forward genetic screens

DNA mismatch repair (MMR) deficiency has been widely utilized in forward genetic screens to identify drug resistance mutations and elucidate the mechanisms of action of cytotoxic small molecules. However, MMR deficiency generates a characteristic mutational signature enriched for C>T transitions that precludes saturation of mutagenesis. We hypothesized that expression of proofreading deficient DNA polymerase epsilon, as has been observed in patients with biallelic MMR deficiency, would enhance mutagenesis and enable identification of new resistance mutations and cytotoxin mechanisms. Here, we combine auxin-inducible degradation of Msh2 with doxycycline-inducible expression of the proofreading-deficient Pol{varepsilon}P286R mutant in murine small cell lung cancer (SCLC) cells. Simultaneous MMR deficiency and mutant Pol{varepsilon} expression markedly increased the emergence of bortezomib-resistant clones relative to either perturbation alone and targeted sequencing of Psmb5 in bortezomib-resistant clones identified recurrent mutations previously reported in chemical mutagenesis-based resistance screens. We next applied this platform to investigate resistance to lurbinectedin, a clinically relevant therapy for SCLC. Whole-exome sequencing revealed recurrent loss-of-function alterations in nucleotide excision repair (NER) genes, most notably Ercc5 and Ercc4, implicating NER deficiency as a major mechanism of lurbinectedin resistance and supporting a central role for NER in mediating lurbinectedin-induced cytotoxicity. Collectively, these findings establish inducible ultramutagenesis as a powerful and versatile platform for the unbiased discovery of drug resistance mechanisms and therapeutic vulnerabilities.

Cancer Biology↗

bioRxiv2026

REPEATED MARINE-TO-FRESHWATER FISH TRANSITIONS REVEAL PALEOENVIRONMENTAL MODULATION OF ADAPTIVE RADIATION

Tropical rivers in Australia and New Guinea (Sahul) provide a rare natural experiment in vertebrate evolution: unlike other continental systems, their freshwater ichthyofaunas are composed almost entirely of marine-derived lineages rather than primary freshwater fishes. This unique biogeographic setting enables replicated tests of why some marine-to-freshwater transitions give rise to extensive adaptive radiations whereas others remain species-poor, and whether these outcomes reflect ecological opportunity or temporally structured paleoenvironmental constraints. Using a densely sampled, time-calibrated phylogenomic framework spanning 2,303 teleost species, we identified a likely range of 27-34 marine-to-freshwater transitions during the Cenozoic, including a pronounced Middle Miocene peak (16-11 Ma). Although ecological opportunity in Sahul rivers enabled repeated colonization in the absence of dominant primary freshwater incumbents, younger freshwater lineages nevertheless diversify faster than older ones, contradicting the expectation that early arrivers should undergo elevated diversification when accessing vacant niche space. Although some colonizations coincide with bursts of speciation consistent with adaptive radiation, many yielded few species despite long residence times. Functional trait analyses likewise revealed no consistent relationship between colonization timing, ecological breadth, or diversification rate, although expanded functional space characterizes previously proposed Sahul adaptive radiations. Comparisons with paleoenvironmental curves indicate that colonization success correlates with sea-level minima and low-oxygen conditions, suggesting that Earth history dynamics modulated when ecological opportunity was accessible. Our results show that although ecological opportunity enabled repeated freshwater invasions into the Sahul region, diversification outcomes are governed by the interaction of paleoenvironmental dynamics and possibly lineage-specific traits, generating stark asymmetries in freshwater radiations. Significance statementTropical rivers in Australia and New Guinea host one of the most unusual continental freshwater fish assemblages on Earth, composed almost entirely of marine-derived lineages. This system allows asking why some colonizing lineages diversify dramatically while others remain species-poor on a continental scale. Using large-scale phylogenomic and functional trait data, we show that early arrival alone does not predict diversification success. Instead, the lineages that radiate most successfully are those whose arrival coincides with windows of paleoenvironmental opportunity created by sea-level and oxygen fluctuations. These results reveal that the fates of colonizing lineages are shaped not only by ecological opportunity, but also by Earth-history dynamics that govern when, where, and how species can invade and diversify.

evolutionary biology↗

bioRxiv2026

Rapid in vitro synthesis of DNA templates via Sidewinder for polyadenylated Hantavirus mRNA vaccine candidates

As the recent COVID-19 pandemic illustrated, zoonotic viruses and other pathogens pose a credible threat to public health. Recent advancements in vaccine technology, particularly mRNA vaccines, provide key tools for an effective and swift public health response. Although mRNA vaccines can be developed more quickly than traditional vaccines, fast and accurate construction of DNA templates for these vaccines remains a critical bottleneck. Using our novel DNA assembly technology, Sidewinder, we rapidly designed and built multiple mRNA vaccine candidates to guard against a potential outbreak of Hantavirus (ANDV). We successfully constructed the DNA templates from oligo pools and produced the mRNA for three vaccine candidates in just 2 days after delivery of the synthetic DNA oligos.

biochemistry↗

bioRxiv2026

HIRA-mediated H3.3 deposition preserves hepatocyte cell identity during liver aging

Age-associated functional decline is partly driven by progressive chromatin degeneration. Maintenance of chromatin integrity preserves cell identity and promotes healthy aging, but through different mechanisms in proliferating and non-proliferating cells. However, specific mechanisms of chromatin maintenance and their compensatory capacity in proliferating and non-proliferating cells are undefined. The histone chaperone HIRA deposits the histone variant H3.3 in a DNA replication-independent manner, leading to its accumulation in aging, non-proliferating cells. Here, we show that hepatocyte-specific loss of HIRA causes loss of cell identity, metabolic dysfunction, and accelerated fibrotic pathology with age. Transcriptomic and epigenomic analyses indicate that HIRA-H3.3 preserves chromatin integrity and sustains transcription of highly expressed genes, including cell identity genes. Partial hepatectomy, associated with induced proliferation, restores identity of HIRA knockout livers with compensatory deposition of canonical histones H3.1/2. Together, these results demonstrate that HIRA-mediated H3.3 deposition is essential for safeguarding cell identity and tissue function during aging of non-proliferating cells, but this function can be rescued by tissue regeneration and associated cell proliferation. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=124 SRC="FIGDIR/small/710643v1_ufig1.gif" ALT="Figure 1"> View larger version (29K): org.highwire.dtl.DTLVardef@a2a26aorg.highwire.dtl.DTLVardef@154e5aeorg.highwire.dtl.DTLVardef@b315a7org.highwire.dtl.DTLVardef@152bca4_HPS_FORMAT_FIGEXP M_FIG C_FIG

genomics↗

bioRxiv2026

Histone variant H2A.Z mutant suppresses the senescence-associated secretory phenotype

Cellular senescence features a durable cell-cycle arrest and a pro-inflammatory senescence-associated secretory phenotype (SASP) driven in part by chromatin remodeling. The histone variant H2A.Z plays an essential role in regulating gene expression through modulating nucleosome dynamics and is known to regulate the expression of cell cycle genes during the early stages of cellular senescence. However, how the intrinsic stability of H2A.Z-containing nucleosomes plays a role in the establishment of the senescent phenotype remains unexplored. To investigate this, we employed H2A.Z R80C, a H2A.Z mutant that destabilizes nucleosomes by disrupting histone-DNA interactions. We observed that expression of H2A.Z R80C causes suppression of SASP in senescent primary human fibroblasts, without affecting expression of cell cycle genes. H2A.Z knockdown did not suppress the SASP, demonstrating that SASP suppression is likely due to altered stability of H2A.Z-containing nucleosomes rather than loss of H2A.Z function. Mechanistically, SASP suppression is linked to decreased H3K27ac at SASP gene loci. These findings offer a novel avenue for understanding and manipulating the SASP during aging and other senescence-related pathologies.

molecular biology↗

bioRxiv2026

AADAT-Driven Metabolic Control of Malate and CoQ10 Shapes Immune Evasion in Triple-Negative Breast Cancer

Compared to other subtypes of breast cancer, triple-negative breast cancers (TNBC) have fewer treatment options and exhibit a worse prognosis. Through integrated transcriptomic, metabolomic, immunohistochemical, spatial, and clinical analyses, we identify the mitochondrial enzyme, -aminoadipate aminotransferase (AADAT) as a previously unrecognized metabolic immune checkpoint in TNBC. AADAT mRNA and protein were significantly upregulated in human TNBC, and high AADAT expression was associated with reduced intra-tumoral CD8 T-cell density and inferior survival. Genetic silencing of AADAT in orthotopic murine TNBC models curtailed primary tumor growth and distant metastasis in a CD8 T-cell-dependent manner, enhanced effector T-cell activation, and sensitized tumors to dual PD-1/CTLA-4 blockade. Mechanistically, unbiased metabolomics showed increased malate levels after AADAT knockdown. Additionally, 4-hydroxyphenylpyruvate, an essential precursor for coenzyme Q10(CoQ10) biosynthesis, decreased following AADAT knockdown, suggesting an impaired mitochondrial electron transport chain. CoQ10 supplementation restored metabolic balance and reversed malate accumulation caused by AADAT knockdown, indicating that AADAT helps maintain CoQ10-supported redox homeostasis, thereby preventing malate buildup and export. Notably, malate addition directly boosted CD8 T-cell oxidative metabolism, increased the NAD/NADH ratio and reactive oxygen species, and augmented TNF- and IFN-{gamma} production. In vivo, malate supplementation in drinking water phenocopied AADAT knockdown, restored the response to paclitaxel plus anti-PD-1 therapy in multiple independent syngeneic TNBC models with de novo or acquired resistance to immunotherapy, reduced tumor burden, and prolonged survival. In patient cohorts, higher spatially clustered intra-tumoral malate is associated with co-localization of functional CD8 T cells, decreased exhausted T-cell neighborhoods, and superior post-chemotherapy outcomes. These data position AADAT as a central metabolic orchestrator of immune escape in TNBC and nominate oral malate as a readily translatable adjuvant to reverse chemo-immunotherapy resistance in TNBC. Statement of SignificanceAADAT defines a metabolic-immune axis driving immune evasion and therapy resistance in triple-negative breast cancer. Blocking AADAT or administering oral malate reactivates CD8 T-cell immunity and sensitizes chemo-immunotherapy-resistant tumors to these agents. These findings uncover a readily translatable metabolic vulnerability with potential to improve outcomes for patients with aggressive breast cancer subtypes.

cancer biology↗

bioRxiv2026

Deep learning-guided design of cell type-specific AAV promoters

Precise cell type targeting is critical for both clinical and experimental applications of adeno-associated viral (AAV) vectors, yet engineering vectors with cell type-specific activity remains a challenge. Here, we compared three strategies leveraging single-cell chromatin accessibility data to design cell type-specific AAV promoters, including a deep learning-based method to generate de novo regulatory sequences. When applied to target retinal ganglion cells or horizontal cells in mouse retina, deep learning-guided design consistently outperformed rational approaches, yielding synthetic promoters with stronger and more specific expression in vivo. Synthetic AAV promoters supported diverse transgenes, enabling the recording and ablation of targeted cells. Promoter activity was also maintained in human retinal organoids, suggesting that deep learning-designed sequences may be suitable for translation. Our findings highlight the potential of deep learning to synthesize cell type-specific AAV promoters and establish a versatile platform for cell type targeting with broad implications for gene therapy and basic research.

synthetic biology↗

bioRxiv2025

Aging-induced hepatocyte CD44 drives IL6/STAT3 signaling and associates with impaired neighboring T cell function.

Liver cancer incidences increase dramatically beyond 55 years of age, suggesting that age-associated changes contribute critically to tumor initiation. However, the mechanisms linking liver aging and cancer initiation are not well defined. This study investigates the role of CD44, a marker of liver tumor-initiating cells (TIC), in age-associated liver pathophysiology. Aged livers showed accumulation of CD44-expressing hepatocytes exhibiting enrichment of immune modulatory genes and activation of the immunosuppressive IL6/JAK/STAT3 pathway. Indeed, in adoptive transfer assays, antigen-exposed CD8+ T cells mounted a lower IFN-{gamma} response in aged livers than in young livers, indicating an immunosuppressive aged milieu. Concordantly, spatial analyses showed that the proximal neighbourhoods of Cd44-expressing hepatocytes are enriched in T cells exhibiting reduced cytokine and chemokine gene expression. Finally, hepatocyte-specific knock out of Cd44 mitigated the IL6/JAK/STAT3 gene signature in aged livers. Overall, these findings suggest that CD44 expression in aged hepatocytes promotes activation of the immunosuppressive IL6/JAK/STAT3 pathway and this is associated with impaired T cell effector function.

cell biology↗

bioRxiv2025

Aging alters tumor cell - T cell crosstalk to promote breast cancer progression

Age is a dominant risk factor for all major breast cancer subtypes. However, the mechanisms by which aging influences tumor development remain unclear. Using a novel mouse model whereby breast cancer is induced in situ in young and old wild-type mice via intraductal delivery of a lentivirus encoding the HER2/neu oncogene, we found that old mice exhibited a higher oncogene-induced tumor burden than young mice. Old tumor cells showed reduced expression of interferon-related genes, particularly the T cell-recruiting chemokines Cxcl9 and Cxcl10, linked to their altered chromatin accessibility. CXCL9/10 expression also declined with age in human HER2+ tumors. Correspondingly, old tumors exhibited fewer T cells within tumor lesions. Targeted interventions showed that decreased expression of Cxcl9/10 is responsible for reduced T cell infiltration and weakened anti-tumor immunity. These results show how aged tumor cells are impaired in their recruitment of immune cells, leading to a defective anti-tumor immune response.

cancer biology↗

bioRxiv2025

Replication of seizure-suppressing effects of alpha-linolenic acid on the Drosophila melanogaster paraShudderer mutant

Voltage-gated sodium channels are essential for healthy nervous system function. Mutations in voltage-gated sodium channels are associated with a range of seizure conditions. The genetics of seizure conditions are complex and often challenging to study or replicate in animal models. The Drosophila melanogaster gene paralytic (para) is the sole voltage-gated sodium channel gene in flies. The paraShudderer allele causes dominant seizure activity manifest in adult morphology and behavior. In this study we replicated previous findings of paraShudderer hyperexcitability and the ability to suppress this activity with dietary supplementation of an omega-3 fatty acid, alpha-linolenic acid (ALA). Our results support the robustness of the paraShudderer phenotype and the replicability of findings across separate lab environments.

neuroscience↗

bioRxiv2025

Targeting CyclinD1-CDK6 to Mitigate Senescence-Driven Inflammation and Age-Associated Functional Decline

Cellular senescence contributes to aging and age-related diseases by driving chronic inflammation through the Senescence Associated Secretory Phenotype (SASP) and interferon-stimulated genes (ISGs). Cyclin D1 (CCND1), a key cell cycle regulator, is paradoxically upregulated in these non-proliferating cells. We show that CCND1 and its kinase partner CDK6 drive SASP and ISG expression in senescent cells by promoting DNA damage accumulation. This leads to the formation of cytoplasmic chromatin fragments (CCFs) that activate pro-inflammatory CGAS-STING signaling. The tumor suppressor p53 (TP53) and its target p21 (CDKN2A) antagonize this CCND1-CDK6-dependent DNA damage accumulation pathway to suppress the SASP. In aged mouse livers, senescent hepatocytes show increased Ccnd1 expression. Hepatocyte-specific Ccnd1 knockout or treatment with the Cdk4/6 inhibitor Palbociclib reduces DNA damage and ISGs in aged mouse liver. Notably, Palbociclib also suppresses frailty and improves physical performance of aged mice. These findings reveal a novel role for CCND1/CDK6 in regulating DNA damage and inflammation in senescence and aging, highlighting it as a promising therapeutic target.

cell biology↗

bioRxiv2025

Rapamycin Reverses the Hepatic Response to Diet-Induced Metabolic Stress That Is Amplified by Aging.

Aging is associated with increased susceptibility to metabolic stress and chronic liver disease, yet the interactions between age and metabolic stressors and the potential for ameliorating interventions remain incompletely understood. Here, we examined the hepatic response of young (7-month-old) and old (25-month-old) C57BL/6 male mice to a 9-week high-fat diet (HFD) and assessed whether rapamycin, a well-established pro-longevity intervention, could mitigate age-exacerbated effects. While both age groups developed metabolic-associated steatohepatitis (MASH), older mice displayed more severe hepatic steatosis, inflammation, and transcriptional dysregulation. Transcriptomic profiling of whole livers and purified hepatocytes revealed that aging amplifies HFD-induced inflammatory and metabolic gene expression changes, including activation of immune pathways and suppression of metabolic pathways. Notably, treatment of aging mice with rapamycin reversed the majority of HFD-driven transcriptional alterations, including upregulation of pro-inflammatory regulators such as Stat1, and dysregulation of metabolic gene networks. Rapamycin also reduced hepatosteatosis, total body weight, and a tumorigenic transcriptomic signature associated with hepatocellular carcinoma risk. These findings demonstrate that aging intensifies hepatic sensitivity to metabolic stress and identify rapamycin as a promising therapeutic to counteract age-related liver dysfunction and MAFLD progression.

cell biology↗

bioRxiv2025

Factors Influencing Monoclonal Antibody Pharmacokinetics Across Varying Immune Perturbations

The development of continuous-release devices or injectables for the long-term delivery of biologics is of great interest, especially monoclonal antibodies (mAbs) that require frequent, high-dose injections. Preclinical testing of these technologies in murine models is necessary for clinical translation; however, xenogeneic responses to the mAb and foreign body responses to the implants or injectables can confound results. Immune system knockout (KO) models that affect immune cells are often used in these experiments, but the effects of KO models on mAb pharmacokinetics (PK) are not well characterized. Here, we investigated the PK profile of the human mAb 3BNC117 after intravenous, subcutaneous, and intraperitoneal injections in four mouse strains: BL6, BCD, RAG2, and NSG mice. Noncompartmental analysis was used to quantify differences in PK between each mouse strain. Strikingly, both BL6 and NSG mice exhibited significantly higher mAb clearance compared to the other two strains. To better understand these differences, we developed a minimally physiological based PK model of mAb PK and estimated model parameters using nonlinear mixed effects modeling. The fitted model parameters illustrated how specific processes change in each strain, including the change in clearance rates over time in BL6 and differences in mAb lymphatic uptake in NSG mice. We then used simple allometric scaling relationships to assess which strains were reasonably predictive of human mAb PK. NSG and BL6 mice were found to be unpredictive of human PK, unlike RAG2 and BCD mice. Overall, these results highlight the importance of selecting an appropriate KO strain for preclinical mAb evaluation and demonstrate that RAG2 and BCD strains are suitable mouse models for investigation of mAb PK. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=64 SRC="FIGDIR/small/651349v1_ufig1.gif" ALT="Figure 1"> View larger version (16K): org.highwire.dtl.DTLVardef@138af32org.highwire.dtl.DTLVardef@763196org.highwire.dtl.DTLVardef@1b17331org.highwire.dtl.DTLVardef@10199e9_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2025

The genetic basis for synchronized time perception in plant populations

Synchronised developmental timing is important for ensuring crop uniformity and high yields. However, climate change is leading to crops being grown at different latitudes, varying their exposures to photoperiods over seasons and impacting developmental timings. We investigated whether the response of circadian rhythms in seedlings to changes in photoperiod would enable us to predict the timing and synchronization of flowering. Indeed, we show that the same Quantitative Trait Loci (QTLs) are associated to circadian traits in seedlings and developmental traits during bolting, using the first recombinant inbred lines (RILs) between African and European Arabidopsis lineages, spanning diverse latitudes. Two QTLs contain K-Homology Domain RNA binding proteins (KH17, KH29) and are associated with splicing variants in known flowering genes, MADS AFFECTING FLOWERING2 and 3 (MAF2, MAF3), including generating chimeric transcripts, a potential mechanism for accelerated proteome evolution. Natural variants in KH17, including in its prion-like domain, are associated with de-coupling the mean and synchronization of flowering time, enabling greater adaptation of population-level heterogeneity in developmental timings. Our results suggest that circadian traits in seedlings could be used to screen for agriculturally relevant developmental traits in mature plants, enabling efficient breeding of climate-resilient crops.

plant biology↗

bioRxiv2024

Activated Interferon Signaling Suppresses Age-Dependent Liver Cancer

Age is a major risk factor for liver cancer, as is the case for most adult human cancers. However, the underlying mechanisms are not well defined. A better understanding of the role of aging in liver and other cancers can facilitate approaches for risk assessment, early detection and prevention. We hypothesize that age-driven changes render aged liver more sensitive to oncogenic stress and hence tumorigenesis. To investigate how the liver changes with age, we documented the immune profile, transcriptome and epigenome of healthy livers from both young and aged mice, revealing pronounced alterations with aging. Notably, in aged hepatocytes, we identified heightened interferon (IFN) signaling, as well as simultaneous tumor suppressor and oncogene signaling at both bulk and single cell level, suggestive of an aged liver that is poised for neoplasia. To challenge this seemingly poised state, we employed adeno-associated virus (AAV)-mediated expression of a c-Myc oncogene in young and aged mouse liver hepatocytes in vivo. Analysis of aged hepatocytes expressing c-Myc revealed further elevated expression of IFN Stimulated Genes (ISGs). This ISG upregulation was evident in multiple models of oncogenic stress and transformation in older mice and also observed in aged humans with Metabolic dysfunction-Associated Steatohepatitis (MASH). We determined that Stat1 is both necessary and sufficient for the age specific elevated ISG expression in old wild type mice. Remarkably, inhibiting Jak/Stat signaling alongside ectopic c-Myc expression led to high-grade hepatocyte dysplasia and tumor formation, selectively in aged mice. Together, these results suggest that an aged liver is in a state of "precarious balance", due to concurrent activation of oncogenic and tumor suppressor pathways, but protected against neoplastic progression by IFN-signaling. Age-dependent activation of IFN signaling has been observed in many tissues and recent studies have demonstrated its detrimental consequences on aging, raising the question as to why IFN-signaling is activated during aging. We propose that aged tissues are intrinsically at higher risk of cancer and age-dependent activation of IFN-signaling is an adaptive process to protect from tumorigenesis, but one that also has maladaptive consequences.

cancer biology↗