Biology subjects

Danhorn, T.

Publications and source records attributed to Danhorn, T..

7 recordsLinked to original sources

bioRxiv2026

Conserved transcriptomic heat stress response signatures in coral recruits selectively bred from thermally distinct broodstock in a low-differentiation system

Thermal history provenancing can guide the choice of parental broodstock for selective breeding of corals from distinct reefs and has been proposed as an intervention for enhancing climate resilience. However, the genetic and molecular mechanisms underlying resultant offspring responses to heat stress, particularly during early life stages, remain poorly understood. Here, we generated Acropora tersa larvae and recruits by crossing parental colonies from the historically warmer Martin Reef and cooler Davies Reef and assessed the effects of within- and between-reef crosses on genetic diversity and transcriptional responses to heat stress. Genome-wide single nucleotide polymorphism analyses showed that broodstock from Martin and Davies Reefs were weakly differentiated (FST = 0.008) and exhibited comparable heterozygosity, as did all larval offspring groups. Transcriptomic analyses of recruits exposed to heat stress (32 {degrees}C for 36 days) revealed that both within- and between-reef offspring groups activated conserved stress-response pathways, with seven genotype-independent heat-responsive genes detected across all offspring groups. Differential expression and enrichment analyses showed induction of defence, protein homeostasis, intracellular transport, and metabolic processes alongside repression of growth- and signalling-related functions, consistent with the Type A General Coral Stress Response. Taken together, these findings suggest that the benefits of thermal history provenancing-informed selective breeding may be limited in low-differentiation systems and that targeted pre-screening of broodstock may help capture functional genetic variation relevant to restoration applications.

genomics↗

bioRxiv2025

PARP1 and PARP2 are dispensable for DNA repair by microhomology-mediated end-joining during mitosis.

Poly ADP-ribose polymerase (PARP) inhibitors are standard of care treatment for cancers with homologous-recombination deficiencies. Yet, as tumors develop resistance, complementary strategies are emerging, including targeting microhomology-mediated end joining (MMEJ). Given that PARP1 is widely described as a key promoter of MMEJ, one would expect PARP inhibition to suppress MMEJ--potentially making MMEJ inhibition redundant. MMEJ was originally described as a backup pathway, with seminal work linking PARP1 to MMEJ conducted in NHEJ-deficient cells, where MMEJ can be reactivated in G1. However, we now appreciate that MMEJ is a mitotic repair mechanism, but the function of PARP1 in this context remains unclear. Here, we systematically explore the effect that PARP/PARPi have on MMEJ activity in cells with intact NHEJ. Surprisingly, PARP inhibition leads to elevated Pol{theta}-dependent MMEJ levels at ISceI-mediated DSBs, which we find is due to PARP1s regulation of competing pathways at these breaks. Importantly, we show that PARP is dispensable for MMEJ at double-ended DSBs and is expendable for repair of DSBs during mitosis. Altogether, this data shifts the understanding of PARPs role in MMEJ and DNA repair pathway choice. Moreover, we believe this data further strengthens a rationale for PARPi/MMEJi combinatorial drug treatment in HR-deficient cancers.

molecular biology↗

bioRxiv2023

Combination CDC-like kinase inhibition (CLK)/Dual-specificity tyrosine-regulated kinase (DYRK) and taxane therapy in CTNNB1-mutated endometrial cancer

SM08502 (cirtuvivint) is a novel pan CDC-like kinase (CLK) and Dual specificity tyrosine kinase (DYRK) inhibitor that targets mRNA splicing and is optimized for Wnt pathway inhibition. Previous evaluation of single agent CLK/DYRK inhibition (SM04690) demonstrated inhibition of tumor progression and {beta}-catenin/TCF transcriptional activity in CTNNB1-mutant endometrial cancer (EC). In-vitro analysis of SM08502 similarly decreases Wnt transcriptional activity and cellular proliferation while increasing cellular apoptosis. SM08502 is an active single-agent therapy with IC50s in the nanomolar range for all EC cell lines evaluated. Combination of SM08502 with paclitaxel has synergistic effect in vitro, as demonstrated by Combination Index <1, and inhibits tumor progression in four endometrial cancer models (HEC265, Ishikawa, Ishikawa-S33Y, and SNGM). In our in vivo mouse models, Ishikawa demonstrated significantly lower tumor volumes of combination vs SM08502 alone (Repeated Measures one-way ANOVA, p = 0.04), but not vs paclitaxel alone. HEC265, SNGM, and Ishikawa-S33Y tumors all had significantly lower tumor volumes with combination SM08502 and paclitaxel compared to single-agent paclitaxel (Repeated Measures one-way ANOVA, p = 0.01, 0.004, and 0.0008, respectively) or single-agent SM08502 (Repeated Measures one-way ANOVA, p = 0.002, 0.005, and 0.01, respectively) alone. Mechanistically, treatment with SM08502 increases alternative splicing (AS) events compared to treatment with paclitaxel. AS regulation is an important post-transcriptional mechanism associated with the oncogenic process in many cancers, including EC. Results from these studies have led to a Phase I evaluation of this combination in recurrent EC.

cancer biology↗

bioRxiv2021

Dual adhesive unipolar polysaccharides synthesized by overlapping biosynthetic pathways in Agrobacterium tumefaciens

Agrobacterium tumefaciens, is a member of the Alphaproteobacteria that pathogenizes plants, and associates with biotic and abiotic surfaces via a single cellular pole. A. tumefaciens produces the unipolar polysaccharide (UPP) at the site of surface contact. UPP production is normally surface-contact inducible, but elevated levels of the second messenger cyclic diguanylate monophosphate (cdGMP) bypass this requirement. Multiple lines of evidence suggest that the UPP has a central polysaccharide component. Using an A. tumefaciens derivative with elevated cdGMP and mutationally disabled for other dispensable polysaccharides, a series of related genetic screens have identified a large number of genes involved in UPP biosynthesis, most of which are Wzx-Wzy-type polysaccharide biosynthetic components. Extensive analyses of UPP production in these mutants have revealed that the UPP is comprised of two genetically, chemically and spatially discrete forms of polysaccharide, and that each requires a specific Wzy-type polymerase. Other important biosynthetic, processing and regulatory functions for UPP production are also revealed, some of which are common to both polysaccharides, and a subset of which are specific to each species. Many of the UPP genes identified are conserved among diverse rhizobia, whereas others are more lineage specific. Plain language summaryBacteria attach to a wide variety of surfaces including host tissues, via externalized structures described as adhesins. We define a large set of genes involved in synthesis of a complex unipolar adhesin comprised of two distinct polysaccharides, that is required for surface attachment by the plant-associated pathogen Agrobacterium tumefaciens.

microbiology↗

bioRxiv2020

GATA2 regulates mast cell identity and responsiveness to antigenic stimulation by promoting chromatin remodeling at super-enhancers

Mast cells (MCs) are critical effectors of allergic inflammation and protection against parasitic infections. We previously demonstrated that transcription factors GATA2 and MITF are the MC lineage-determining factors (LDTFs). However, it is unclear whether these LDTFs regulate chromatin accessibility at MC enhancer regions. In this study, we demonstrate that GATA2 promotes chromatin accessibility at the super-enhancers of MC identity genes and primes both typical and super-enhancers at genes that respond to antigenic stimulation. We found that the number and densities of GATA2-but not MITF-bound sites at the super-enhancers were several folds higher than that at the typical enhancers. Our studies revealed that GATA2 promotes robust gene transcription to maintain MC identity and respond to antigenic stimulation by binding to super-enhancer regions with dense GATA2 binding sites available at key MC genes.

molecular biology↗

bioRxiv2020

Human and mouse transcriptome profiling identifies cross-species homology in pulmonary and lymph node mononuclear phagocytes

The mononuclear phagocyte (MP) system consists of macrophages, monocytes, and dendritic cells (DCs). MP subtypes play distinct functional roles in steady state and inflammatory conditions. Though murine MPs are well characterized, their pulmonary and lymph node (LN) human homologs remain poorly understood. To address this gap, we created a gene expression compendium across 15 distinct human and 9 distinct murine MPs from lung, LN, blood, and spleen. Human blood MPs and murine spleen MPs served as validation datasets, as the human-mouse MP homologs are relatively well-defined in these tissues. In-depth RNA sequencing identified corresponding human-mouse MP subtypes and determined marker genes shared and divergent across between species counterparts. Unexpectedly, at the gene expression level, only 13-23% of the top 1000 marker genes (i.e., genes not shared across species-specific MP subtypes) overlapped in corresponding human-mouse MP counterparts, indicating a need for caution when translating mouse studies to human gene targets and functions. Lastly, CD88 was useful in both species to distinguish macrophage and tissue monocytes from DCs. Our cross-species gene expression compendium serves as a resource for future translational studies to investigate beforehand whether pursuing specific MP subtypes, or genes will prove fruitful.

immunology↗

bioRxiv2017

The somatically generated T cell receptor CDR3a contributes to the MHC allele specificity of the T cell receptor

Mature T cells bearing {beta} T cell receptors react with foreign antigens bound to alleles of major histocompatibility complex proteins (MHC) that they were exposed to during their development in the thymus, a phenomenon known as positive selection. The structural basis for positive selection has long been debated. Here, using mice expressing one of two different T cell receptor {beta} chains and various MHC alleles, we show that positive selection-induced MHC bias of T cell receptors is affected both by the germline encoded elements of the T cell receptor and {beta} chain and, surprisingly, dramatically affected by the non germ line encoded CDR3 of the T cell receptor chain. Thus, in addition to determining specificity for antigen, the non germline encoded elements of T cell receptors may help the proteins cope with the extremely polymorphic nature of major histocompatibility complex products within the species.

immunology↗