Biology subjects

Roman, A.

Publications and source records attributed to Roman, A..

At least 19 recordsLinked to original sources

bioRxiv2026

Genomic forecasting links climate-associated variation to spring phenology in the European wild apple, a crop wild relative of the cultivated apple

Climate-associated genomic variation is often used as a proxy for adaptive potential, yet whether it reflects adaptation with phenotypic consequences, rather than demography alone, is rarely tested in long-lived species. Genomic offsets forecast climate maladaptation from genotype-environment models but are seldom validated against phenotypes. We combined whole-genome resequencing, SNP and transposable element insertion polymorphism (TIP) variation, landscape genomics, genome-wide association, genomic offset, and common-garden phenotyping in the European wild apple (Malus sylvestris Mill.), a crop wild relative with a complex demographic history, to test this. Results: Of 148 resequenced accessions (135 wild, 13 cultivated), 89 wild individuals formed the core dataset. Population structure was associated with Last Glacial Maximum precipitation rather than contemporary climate, and genetic diversity increased from west to east. Genome-environment associations across 9.75 million SNPs identified climate-associated loci enriched in photoperiod-related flowering-time genes, with limited overlap with phenotype-associated loci. SNP-based genomic offset was associated with bud-break timing in the Saclay common garden (marginal R2 = 0.31), with higher offsets corresponding to earlier bud break, but not with growth or ecophysiological traits. This association depended on Austrian and Romanian populations and was clearest in non-admixed wild individuals. Offsets based on TIPs or glacial climate did not predict measured phenotypes. Conclusions: Climate association, phenotypic relevance, and predictive power of genomic variation are separable. In a long-lived tree, genomic offset predicted spring phenology, a key adaptive trait, but this signal varied across provenances and ancestries and was absent for transposable elements. Genomic offsets can therefore forecast potential phenological maladaptation, provided they are validated against phenotypes such as bud break.

ecology↗

bioRxiv2026

Domestication altered defense responses and host-aphid interaction networks in apples

- Domestication can profoundly reshape plant defense strategies and host-parasite interactions, but its consequences for resistance and coevolution in perennial crops remain poorly understood. We investigated how domestication altered apple responses to its major pest, the rosy apple aphid (Dysaphis plantaginea). - We compared wild (Malus orientalis, two geographically differentiated M. sylvestris populations) and cultivated (cider and dessert M. domestica) apple genotypes against two genetically distinct aphid genotypes, combining controlled infestation experiments with phenotypic measurements, paired host-aphid RNA-seq, co-expression network analysis, and genome-wide selection scans. - Aphid fitness and host resistance varied strongly across host populations: domesticated apples supported higher aphid performance, whereas Romanian M. sylvestris showed the highest resistance, revealing marked host-aphid genotype-specific asymmetric compatibility. Cultivated apples have developed extensive inducible transcriptional defense responses, whereas wild populations showed weaker perturbation despite lower aphid fitness, consistent with more constitutive defense. Host-aphid co-expression analyses identified candidate coevolutionary modules linking host resistance genes under balancing selection with aphid genes under positive selection. - Together, these results demonstrate that apple domestication reshaped defense-associated regulatory networks and modified the adaptive landscape experienced by aphid populations, providing new insight into the evolutionary consequences of perennial crop domestication on host-parasite interactions.

evolutionary biology↗

bioRxiv2026

Efficient CRISPR/Cas9-mediated homology independent sequence replacement in vivo and non-dividing primary cells

Precise sequence replacement in non-dividing cells remains a major challenge for genome editing. Here we show that REPLACE (Rational end-joining protocol delivering a targeted sequence exchange), a homology-independent CRISPR/Cas9-based replacement strategy, enables exon- and gene-scale substitution in primary cells, in vivo tissues and post-mitotic human cardiomyocytes. REPLACE uses two guide RNAs to excise a defined genomic region and inserts a donor lacking homology arms through non-homologous end joining (NHEJ). In primary mouse hepatocytes, REPLACE mediated exon replacement in 35% of all cells. In adult mouse liver, editing efficiency could be increased to [~]20% when Cas9-sgRNA ribonucleoproteins were delivered via engineered virus-like particles (eVLPs) together with an adeno-associated virus (AAV) donor. REPLACE also supported large-segment replacement, enabling one-step exchange of a [~]27-kb mouse Ace2 interval with the human ACE2 coding region in zygotes, followed by germline transmission and tissue-specific expression. Finally, we applied REPLACE to a disease-relevant mutation that is not readily addressable by base editing and was poorly corrected by prime editing in post-mitotic cardiomyocytes. At the LMNA locus, REPLACE corrected the K117fs frameshift mutation in patient-derived post-mitotic cardiomyocytes with precise exon replacement and restored Lamin A/C protein expression and nuclear lamina localization. These findings establish REPLACE as a versatile platform for homology-independent sequence replacement and as a complementary approach for genetic correction in settings where homology-directed repair (HDR), base editing (BE) or prime editing (PE) are inefficient or not applicable.

genomics↗

bioRxiv2026

Microbiota-dependent IFN-L controls uterine and placental immunity.

Precise regulation of uterine immunity is required to support fundamental processes including reproduction and pathogen protection. How the local milieu and constitutive stressors, including the cervicovaginal microbiota, shape the delicate balance underlying uterine immunity is poorly understood. Here, we found that the cervicovaginal microbiota promotes both local immunity and the immunoregulatory activity of interferon lambda (IFN-L) in the uterus. Using murine models, we found a keystone role for IFN-L in constraining the immune tone of this site, in particular of innate lymphoid cells and Th17 cells. Further, in the context of pregnancy, IFN-L enhanced antibacterial responses at maternal-fetal barriers to Streptococcus agalactiae infection, thereby controlling fetal and neonatal transmission. Collectively, this work uncovered how IFN-L integrates microbial signals under both steady state and pregnancy conditions and mediates the essential functions of the uterine immune system - antimicrobial protection and immunoregulation.

immunology↗

bioRxiv2026

Climate drives plasticity and genetic adaptation in apple trees

BackgroundPerennial crops respond to climate change through phenotypic plasticity and local adaptation, yet how these responses are orchestrated at the molecular level and reshaped by domestication remains poorly understood. ResultsWe grew 1,249 seedlings from five populations of M. domestica, M. orientalis, and M. sylvestris under four simulated European climates, quantified 12 phenotypic traits, performed RNA sequencing on 96 individuals, and integrated these data with previously published genome-wide polymorphism data from M. sylvestris to disentangle conserved climate responses from local adaptation. Climate was the dominant driver of phenotypic and transcriptional variation, revealing 344 conserved climate-responsive genes enriched for stress responses, nutrient metabolism, and cell wall biosynthesis. These genes are under strong purifying selection and carry fewer deleterious mutations. In contrast, genome-environment association analyses identified 217 loci associated with temperature and precipitation gradients, only a subset of which showed climate-responsive expression and elevated genomic differentiation. Population-level expression divergence closely mirrored neutral genetic differentiation, indicating that most transcriptomic divergence reflects demographic history rather than adaptive regulatory evolution. Domestication reshaped molecular diversity and mutation load without disrupting the conserved climate-response program. ConclusionsClimate responses in apple are primarily mediated by an evolutionarily conserved transcriptional program maintained by strong purifying selection, whereas local adaptation relies on largely distinct, population-specific loci. These findings reveal that conserved plasticity constitutes the dominant molecular response to climatic variation, whereas local adaptation contributes a secondary, population-specific layer of evolutionary change.

evolutionary biology↗

bioRxiv2025

Cryo-ET Reveals Distinct Gag Lattice Architectures in Virus-like Particles and Immature HIV-1

HIV-1 is released from infected cells as immature virions whose membranes are supported by a Gag lattice. During maturation, this lattice is cleaved by the viral protease to release capsid proteins that assemble into the mature core. The architecture of the Gag lattice is central to this process, and the Gag lattice is targeted by maturation inhibitors that block cleavage. Using cryo-electron tomography, we compared Gag-only virus-like particles (VLPs) with immature HIV-1 virions and found that VLPs assemble denser and more complete lattices, exhibiting a strong correlation between lattice curvature and Gag copy number. In contrast, immature virions incorporate fewer Gag molecules and display weaker coupling between curvature and Gag stoichiometry. These findings show that while Gag alone can form the canonical immature lattice, additional viral components fine-tune lattice organization and curvature, potentially regulating protease accessibility, virion release, and the onset of HIV-1 maturation.

biophysics↗

bioRxiv2025

E2F1-3 activate polyomavirus early transcription and viral replication

Merkel cell polyomavirus (MCPyV) is a DNA virus that establishes a persistent asymptomatic infection during childhood and can cause Merkel cell carcinoma (MCC) later in life. Its Large and Small Tumor antigens (LT, ST), splice variants of a common viral early transcript, drive viral replication and tumorigenesis by binding to and perturbing the function of host proteins. LT binds and inhibits RB1, deregulating E2F activity and host cell cycle control to permit viral replication during S phase. While the functions of LT and ST are relatively well characterized, how their expression is controlled is poorly defined. Here, we discovered that E2F1-3/DP1 dimers bind the MCPyV Non-Coding Control Region (NCCR) via a consensus E2 site close to the LT/ST transcriptional start site. Inhibiting E2F-NCCR binding, either by deleting the E2 site or treatment with a E2F small molecule inhibitor, downregulated LT/ST mRNA and protein expression in MCC cells and in 293A cells transfected with MCPyV. Our findings reveal an E2F/LT/RB1 positive feedback loop that appears to have evolved to support viral replication and is hijacked in MCC cells to promote cellular proliferation. Furthermore, we identified E2 sites in the NCCRs of PyVs closely related to MCPyV, including murine PyV, which mediate E2F/DP binding and potentiate viral early transcription. E2F/DP also bound weakly to the SV40 and BKPyV NCCRs, despite lacking an E2 site. Our findings challenge the prevailing model that PyV LT expression drives S phase entry and suggest, in contrast, that S phase entry stimulates PyV early transcription and replication. Significance statementPolyomaviruses (PyVs) express Large and Small Tumor antigens (LT, ST), splice variants of a common viral early transcript, that drive viral replication and tumorigenesis by binding and perturbing the function of host cells. LTs bind and inhibit RB1 via conserved LxCxE motifs, deregulating E2F activity and host cell cycle control to permit viral replication. Here, we discovered that E2F1-3 bind to the Non-Coding Control Regions (NCCRs) of many, but not all, PyVs to activate LT/ST transcription, revealing an E2F/LT/RB1 positive feedback loop that appears to have evolved to promote viral replication. Our findings challenge the existing paradigm that PyV LT expression drives S phase entry and suggest, in contrast, that S phase entry stimulates PyV LT/ST transcription and replication.

microbiology↗

bioRxiv2025

Simulation and empirical evaluation of biologically-informed neural network performance

Biologically-informed neural networks (BiNNs) offer interpretable deep learning models for biological data, but the dataset characteristics required for strong performance remain poorly understood. For instance, we previously developed P-NET, a BiNN with an architecture based on the Reactome pathway database, and applied this model to predict metastatic status of patients with prostate cancer using somatic mutation and copy number information. It seems likely that including additional relevant signal - e.g., germline variation in this context - should improve model performance, but we currently lack a principled approach to assess whether BiNNs will successfully detect this signal. Here, we developed two simulation frameworks to evaluate the factors that influence BiNN performance - including signal type, signal strength, feature sparsity, and sample size - and empirically tested how integrating germline and somatic data affects the models ability to predict prostate cancer metastatic status. Simulations revealed that small sample size, weak signal strength, and especially extreme feature sparsity limit BiNN performance, and that the model preferentially uses linear over nonlinear signal. Empirically, P-NET performed poorly on sparse germline data, and while adding germline to somatic data did not improve prediction, it improved gene prioritization and model interpretation. Broadly, our simulation frameworks enable systematic evaluation of how dataset-level characteristics affect BiNN performance and provide a principled framework for benchmarking novel methods.

bioinformatics↗

bioRxiv2025

Empirical Evaluation of Single-Cell Foundation Models for Predicting Cancer Outcomes

Foundation models pretrained on large-scale single-cell RNA sequencing data present a promising opportunity to advance translational cancer research. However, their utility in clinically relevant, patient-level single-cell applications remains underexplored. Here, we developed an agentic strategy to systematically evaluate twelve emerging single-cell foundation models (scFMs) and three alternative baseline approaches across seven cancer-specific tasks, including cell-type annotation, cancer subtype classification, and treatment response prediction. We assessed model performance under zero-shot, continual training, and fine-tuning conditions, conducting 1,530 supervised model-fitting runs and 200 unsupervised subsample evaluations. We found that while current scFMs excelled at certain analysis tasks, such as tumor microenvironment cell annotation, they offered limited advantages in predicting clinical and biological outcomes of cancer patients compared to simpler baseline models. These insights highlight the critical role of scFM evaluation on biologically and clinically relevant tasks for precision oncology. Beyond identifying current limitations, this assessment reveals principles that can guide future methodological innovation and the use of expanded cancer single-cell cohorts to build more biologically informed and translationally effective scFMs. The resulting agentic framework supports the autonomous discovery of emerging scFMs and facilitates their standardized integration and evaluation across cancer-related tasks.

cancer biology↗

bioRxiv2025

Gene flow from the European wild apple and selection shaped the domesticated apple (Malus domestica Borkh.) genome

How selection and demography shape genomes of long-lived crops remains largely unresolved. Using apple (Malus domestica) as a model, we integrate 218 whole genomes (68 cultivated dessert/cider; 150 wild: M. sieversii, M. orientalis, M. sylvestris), RNA-seq, and a flowering-time GWAS to resolve how these forces forged the cultivated apple genome. Despite weak neutral differentiation and widespread admixture, dessert and cider apples form distinct gene pools that derive primarily from M. sieversii-M. orientalis rather than European M. sylvestris. We find no evidence of a strong domestication bottleneck, as expected in perennials. Demography-aware selection scans reveal largely non-overlapping targets: dessert shows more hard sweeps at genes linked to fruit quality, disease resistance, and flowering, whereas cider shows proportionally more soft sweeps and balancing selection; RNA-seq differential expression supports these candidates. Wild-to-crop introgression from M. sylvestris is extensive but heterogeneous by context: some introgressed tracts concentrate in hard-sweep regions and approach fixation (consistent with rapid, targeted uptake), whereas others persist at intermediate frequencies with soft-sweep signatures (consistent with diffuse, recurrent introgression of adaptive alleles). Extending to the phenotype, the lead chromosome 9 flowering-time association lies within an introgressed segment near a transposable element and is separated from sweep peaks, consistent with regulatory/polygenic control. Cultivated apples carry a lower predicted deleterious load than wild relatives. Together, these results provide one of the most comprehensive population genomic portraits of a perennial fruit tree domestication, clarifying how selection and adaptive introgression jointly shaped the cultivated apple genome architecture and yielding actionable targets for breeding and conservation. Significance statementPerennial crops are underexplored compared to annuals, leaving open the question of how selection, gene flow, and demography shape their genomes. Using the apple tree (Malus domestica), we analyzed 218 genomes, along with expression and trait data. Despite weak genome-wide differences, dessert and cider apples form distinct gene pools. Widespread gene flow from the European wild apple supplied adaptive alleles, with contrasting dynamics: in cider, a few introgressed DNA segments rose rapidly; in dessert, many variants shifted gradually. Cultivated apples also carry a lower predicted burden of harmful mutations than wild relatives. Together, these results redefine perennial domestication and pinpoint genomic targets to accelerate breeding and conservation.

genetics↗

bioRxiv2025

CNS-Tau Specific Antibodies Illuminate Disease Signatures Across Tauopathies

BackgroundAlternative splicing of the MAPT gene produces distinct tau isoforms in the central and peripheral nervous systems (CNS and PNS), yet their respective biological and pathological roles remain poorly understood. Recent studies suggest that CNS-tau may play a key role in amyloid-{beta} associated neurodegeneration in Alzheimers disease (AD), but the absence of isoform-specific tools has limited both mechanistic insight and biomarker development. We aimed to develop and validate CNS-tau-specific monoclonal antibodies and assess their utility in neuropathology and fluid-based biomarker assays across AD and primary tauopathies. MethodsWe generated six recombinant rabbit monoclonal antibodies targeting a CNS-tau-specific sequence encoded by exons 4 and 5. Specificity and affinity were evaluated via biolayer interferometry, immunoblotting, and tau-expressing HEK293 models. The lead clone, LL-T-1-1, was tested in postmortem brain sections from AD (n = 23), progressive supranuclear palsy (PSP, n = 3), and corticobasal degeneration (CBD, n = 3). A second clone, LL-T-1-5, was optimized for use in plasma assays via an ultrasensitive nanoneedle platform, LoD < 1 pg/ml. ResultsLL-T-1-1 showed nanomolar affinity for CNS-tau and no cross-reactivity with PNS-tau. It selectively labeled dystrophic neurites in AD and all hallmark tau lesions in PSP and CBD without antigen retrieval. LL-T-1-5-based plasma assays revealed CNS-tau levels significantly correlated with cognitive scores (MMSE and QDRS) and differentiated impaired from unimpaired individuals. ConclusionsCNS-tau-specific antibodies LL-T-1-1 and LL-T-1-5 provide new tools for neuropathology and fluid biomarker development across tauopathies.

neuroscience↗

bioRxiv2025

METTL3-mediated m6A modification of DNMT1 enhances ovarian cancer progression

High-grade serous carcinoma (HGSC), the most lethal subtype of ovarian cancer, is often diagnosed at advanced stages owing to its asymptomatic progression and lack of early detection markers. In this study, we identified a critical oncogenic role of the RNA methyltransferase METTL3 and the N6-methyladenosine (m6A) RNA modification pathway in HGSC. Depletion of METTL3 or its binding partner METTL14 impairs ovarian cancer proliferation and tumor progression. Mechanistically, m6A deposition enhances the translation of DNA methyltransferase DNMT1, an epigenetic repressor that silences tumor suppressor genes. Pharmacologic inhibition of DNMT1 led to DNA hypomethylation and upregulation of the tumor suppressors TNFAIP3 and FBXO32. Consistently, METTL3 depletion also increased the expression of these genes supporting a model in which METTL3 sustains oncogenesis by maintaining DNMT1 protein levels and repressing anti-tumor pathways. These findings position METTL3-mediated RNA modifications and DNMT1 as promising therapeutic targets in HGSC.

cancer biology↗

bioRxiv2025

Delta-catenin is required for cell proliferation in virus positive Merkel cell carcinoma cell lines but not in human fibroblasts

Merkel cell carcinoma (MCC) is a highly aggressive neuroendocrine skin cancer often driven by the integration of Merkel cell polyomavirus (MCPyV) into the host genome and the persistent expression of its viral oncoproteins, small tumor (ST) antigen and truncated large tumor (t-LT) antigen. While human fibroblasts support MCPyV replication, the cell of origin for MCC remains unknown. We hypothesized that MCPyV initially replicates in fibroblasts but, in rare cases, infects Merkel cell progenitors, contributing to MCC development. Using TurboID mass spectrometry, we identified {delta}-catenin as a novel ST interactor in fibroblasts. However, while ST binds {delta}-catenin in fibroblasts, this interaction is absent in virus-positive (VP)-MCC cell lines. Despite this, {delta}-catenin is essential for VP-MCC, but not for fibroblast, cell proliferation. We found that fibroblasts predominantly express {delta}-catenin isoform 1, whereas VP-MCC cells mainly express isoform 3. Overexpression of isoform 1 in VP-MCC failed to restore ST binding. {delta}-catenin promotes VP-MCC proliferation by regulating cell cycle gene expression through its interaction with Kaiso, a transcriptional repressor. Additionally, we found that LSD1 (KDM1A) regulates {delta}-catenin isoform 3 expression by modulating ESRP1, a {delta}-catenin splicing factor. Our findings reveal novel host factors involved in MCPyV infection and MCC tumorigenesis, suggesting that the host cell supporting viral replication and the MCC cell of origin may be distinct cell types. ImportanceMerkel cell polyomavirus (MCPyV), the only known human oncogenic polyomavirus, is the primary cause of Merkel cell carcinoma (MCC), a rare and aggressive type of skin cancer. MCC is driven by two viral proteins: small T (ST) and large T (LT). While the virus can replicate in skin fibroblasts, it is still unknown which type of skin cell becomes cancerous. We found that ST binds to a host protein, {delta}-catenin in fibroblasts, potentially playing a role in the virus lifecycle, but this interaction is missing in the cancer cells. Our study provides evidence that the cells in which the virus replicates and causes cancer are different.

cancer biology↗

bioRxiv2024

Polyomavirus ALTOs, but not MTs, downregulate viral early gene expression by activating the NF-κB pathway

Polyomaviruses are small, circular dsDNA viruses that can cause cancer. Alternative splicing of polyomavirus early transcripts generates large and small tumor antigens (LT, ST) that play essential roles in viral replication and tumorigenesis. Some polyomaviruses also express middle tumor antigens (MTs) or Alternate LT ORFs (ALTOs), which are evolutionarily related but have distinct gene structures. MTs are a splice variant of the early transcript whereas ALTOs are overprinted on the second exon of the LT transcript in an alternate reading frame and are translated via an alternative start codon. Merkel cell polyomavirus (MCPyV), the only human polyomavirus that causes cancer, encodes an ALTO but its role in the viral lifecycle and tumorigenesis has remained elusive. Here, we show MCPyV ALTO acts as a tumor suppressor and is silenced in Merkel cell carcinoma (MCC). Rescuing ALTO in MCC cells induces growth arrest and activates NF-{kappa}B signaling. ALTO activates NF-{kappa}B by binding SQSTM1 and TRAF2&3 via two N-Terminal Activating Regions (NTAR1+2), resembling Epstein-Barr virus (EBV) Latent Membrane Protein 1 (LMP1).. Following activation, NF-{kappa}B dimers bind the MCPyV non-coding control region (NCCR) and downregulate early transcription. Beyond MCPyV, NTAR motifs are conserved in other polyomavirus ALTOs, which activate NF-{kappa}B signaling, but are lacking in MTs that do not. Furthermore, polyomavirus ALTOs downregulate their respective viral early transcription in an NF-{kappa}B and NTAR dependent manner. Our findings suggest that ALTOs evolved to suppress viral replication and promote viral latency and that MCPyV ALTO must be silenced for MCC to develop.

microbiology↗

bioRxiv2024

Identification of Fibrinogen as a Plasma Protein Binding Partner for Lecanemab Biosimilar IgG: Implications for Alzheimer's Disease Therapy

ObjectiveRecombinant monoclonal therapeutic antibodies like lecanemab, which target amyloid beta in Alzheimers disease, offer a promising approach for modifying the disease progression. Due to its relatively short half-life, Lecanemab, administered as a bi-monthly infusion (typically 10mg/kg) has a relatively brief half-life. Interaction with abundant plasma proteins binder in the bloodstream can affect pharmacokinetics of drugs, including their half-life. In this study we investigated potential plasma protein binding interaction to lecanemab using lecanemab biosimilar. MethodsLecanemab biosimilar used in this study was based on publicly available sequences. ELISA and Western blotting were used to assess lecanemab biosimilar immunoreactivity in the fractions human plasma sample obtained through size exclusion chromatography. The binding of lecanemab biosimilar to candidate binders was confirmed by Western blotting, ELISA, and surface plasmon resonance analysis. ResultsUsing a combination of equilibrium dialysis, ELISA, and Western blotting in human plasma, we first describe the presence of likely plasma protein binding partner to lecanemab biosimilar, and then identify fibrinogen as one of them. Utilizing surface plasmon resonance, we confirmed that lecanemab biosimilar does bind to fibrinogen, although with lower affinity than to monomeric amyloid beta. InterpretationIn the context of lecanemab therapy, these results imply that fibrinogen levels could impact the levels of free antibodies in the bloodstream and that fibrinogen might serve as a reservoir for lecanemab. More broadly, these results indicate that plasma protein binding may be an important consideration when clinically utilizing therapeutic antibodies in neurodegenerative disease.

neuroscience↗

bioRxiv2023

Sequential colonization events with restricted gene flow in a widespread European carnation species

The key questions relating to the evolutionary processes underlying plant colonization success pertain to the geographic origin of the source population(s), the location of the migration routes, the extent to which genetic diversity is reduced via founder effects, and the extent of gene flow among populations during expansion. However, these questions must still be addressed for perennial herbaceous plants with large geographic distributions. We investigated the colonization history of Dianthus carthusianorum (the Carthusian Pink), one of the most widespread European carnation species. We called genome-wide 236,964 SNPs from a large sample across the D. carthusianorum distribution range, and used up-to-date population genomics approaches (approximate Bayesian computation Random-Forest method, ABC-RF) to infer population demographic history. Spatial genetic structure and diversity analyses and demographic inferences indicated successive East-West colonization events by the Carthusian Pink. ABC-RF also revealed gene flow during colonization, but only among geographically close populations. This study provides important insights into the colonization processes of herbaceous perennial species belonging to one of Europes most diverse plant genera.

evolutionary biology↗

bioRxiv2023

The catalytic-independent function of LSD1 modulates the epigenetic landscape of mouse embryonic stem cells

Lysine-specific histone demethylase 1 (LSD1), which demethylates mono- or di-methylated histone H3 on lysine 4 (H3K4me1/2), is essential for early embryogenesis and development. Here we show that LSD1 is dispensable for embryonic stem cell (ESC) self-renewal but is required for ESC growth and differentiation. Reexpression of a catalytically-dead LSD1 (LSD1MUT) recovers the proliferation capability of ESCs, yet the enzymatic activity of LSD1 is essential to ensure proper differentiation. Indeed, a gain of H3K4me1 in Lsd1 knockout (KO) ESCs does not lead to major changes in global gene expression programs related to stemness. However, ablation of LSD1 but not LSD1MUT results in decreased DNMT1 and UHRF1 proteins coupled to global hypomethylation. We show that both LSD1 and LSD1MUT control protein stability of UHRF1 and DNMT1 through interaction with the ubiquitin-specific peptidase 7 (USP7) and, consequently, inhibiting DNMT1 and UHRF1 ubiquitylation. Our studies elucidate for the first time a novel mechanism by which the scaffolding function of LSD1 controls DNA methylation in ESCs.

molecular biology↗

bioRxiv2022

Multi-dimensional structure of C. elegans thermal learning

Quantitative models of associative learning that explain behavior of real animals with high precision have turned out very difficult to construct. We do this in the context of the dynamics of the thermal preference of C. elegans. For this, we quantify C. elegans thermotaxis in response to various conditioning parameters, genetic perturbations, and operant behavior using a fast, high-throughput microfluidic droplet assay. We then model this data comprehensively, within a new, biologically interpretable, multi-modal framework. We discover that the dynamics of thermal preference are described by two independent contributions and require a model with at least four dynamical variables. One pathway positively associates the experienced temperature independently of food and the other negatively associates to the temperature when food is absent.

biophysics↗