Biology subjects

Islam, S.

Publications and source records attributed to Islam, S..

At least 19 recordsLinked to original sources

bioRxiv2026

In silico subtractive genomics and reverse vaccinology approach reveal outer membrane proteins OMP47 and LptD as dual-purpose drug and vaccine targets in Pasteurella multocida Pm70

Drug targets and vaccines for bacterial diseases are challenging to develop. Computational subtractive genomics and reverse vaccinology offer a viable substitute for conventional drug and vaccine development approaches. In recent years, Pasteurella multocida, a Gram-negative pathogen responsible for severe infections in humans along with major diseases in livestock and poultry, has developed resistance to multiple drugs. As a result, there is an urgent demand for research into reliable, efficient, highly potent, and cost-effective strategies to combat the rise of Pasteurella multocida infections. To address this, the present study integrated an in silico subtractive genomics and reverse vaccinology workflow to pinpoint proteins with potential value as both drug and vaccine targets. From the complete Pasteurella multocida Pm70 proteome, we identified 446 proteins that had no similarities with human proteins, out of which 129 were found to be essential for the pathogens survival. These 129 proteins are therefore potential candidates for drug development. Further metabolic pathway analysis, virulence potential, subcellular localization, and structural analyses revealed two outer membrane proteins, namely, 47 kDa outer membrane protein and lipopolysaccharide-assembly protein LptD, as promising candidates for therapeutic development. Subsequent antigenicity analysis revealed both outer membrane proteins as potential vaccine targets, exhibiting highly favorable antigenicity scores. Candidate B- and T-cell epitopes were systematically mapped from these two targets based on antigenicity, immunogenicity, toxicity, and allergenicity potential and only high-confidence epitopes were assembled using adjuvants and class-specific linkers to construct the final multi-epitope vaccine (MEV). The designed MEV construct was demonstrated to be highly antigenic, non-toxic and non-allergenic to humans, while possessing favorable structural and physicochemical properties, and exhibited strong binding interactions with human toll-like receptors with minimal molecular deformability. Although further experimental validation is recommended to fully assess their efficacy, the present study establishes a solid foundation for the development of novel therapeutics and vaccine candidates against P. multocida, ultimately contributing to the reduction of its rising infections.

bioinformatics↗

bioRxiv2026

Length scale of cellular activity determines signatures of epithelial remodeling

Cellular activity drives epithelial fluidization -- a widespread phenomenon observed during tissue development, remodeling, and repair both in vivo and in vitro. Yet the physical origins and spatial organization of active forces vary widely across biological systems and are often represented by a single generic mechanism in theoretical models. Here, using an active vertex model, we systematically compare four modes of epithelial activity spanning subcellular to tissue scales: apolar motility, polar motility, fluctuating contractility, and mechanochemical regulation. Although all four mechanisms drive the same global transition from a solid-like rectangular tissue to a fluid-like circular morphology, they reach this state through distinct pathways -- differing in the rates and topology of junctional rearrangements, cell elimination, and collective motion and leave distinguishable signatures in tissue architecture, cell dynamics, and mechanical relaxation. Among these observables, spatial velocity correlations directly capture the spatial organization of activity: their correlation length and functional form together resolve all four mechanisms. The robustness of these signatures across activity strengths suggests that spatial velocity correlations offer an experimentally accessible means of identifying the physical origin of epithelial activity from live-cell imaging alone.

biophysics↗

bioRxiv2026

BCL11B targeting in tumor CD8+ T cells amplifies anti-tumor response by blocking exhaustion while promoting stemness and cytotoxicity

Tumor infiltrating CD8+ T cells (TILs) progress to a state of terminal exhaustion (Ttex) which have impaired functionality and are nonrenewable. However their precursors (Tpex) are renewable and can generate efficient effector cells. We started from the observation that melanoma patients undergoing therapy with checkpoint inhibitors show increased survival when their T cells have low BCL11B mRNA. In line with this, ablation of Bcl11b in CD8+ TILs conferred a superior anti-tumor response in murine melanoma and ovarian cancer models. Bcl11b KO TILs failed to progress to the Ttex state and retained elevated stemness. Bcl11b exerted its role by repressing expression of essential transcription factors (TF) controlling stemness, and conversely by promoting expression of exhaustion-associated TFs and inhibitory receptor genes, through complex epigenetic control. In addition, Bcl11b KO CD8+ T cells showed increased Ag-specific cytolytic activity and elevated Gzmb and Prf1 proteins, but no increase in their mRNAs, however presented higher expression of genes with role in translation. Furthermore, CRISPR-CAS9-mediated deletion of BCL11B in human TILs from a patient with poor response to adoptive cell therapy with autologous TILs, improved their cytolytic activity and promoted expression of the stemness-associated TF TCF1, underlying its potential therapeutic use. HIGHLIGHTS- Adoptive transfer of Bcl11b KO CD8+ TILs surpasses WT in tumor burden reduction - Bcl11b ablation reprograms TILs and impairs the progression to Ttex state - Bcl11b KO CD8+ T cells have elevated cytotoxicity and kill only Ag-MHCI targets - BCL11B deletion in nonresponder ACT-TIL improves cytolytic activity and elevates TCF1 GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=64 SRC="FIGDIR/small/742578v1_ufig1.gif" ALT="Figure 1"> View larger version (33K): org.highwire.dtl.DTLVardef@c3b965org.highwire.dtl.DTLVardef@1c09d75org.highwire.dtl.DTLVardef@a19748org.highwire.dtl.DTLVardef@d2fd6b_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2026

Cytoplasmic capping enzyme targeted, hypoxia-responsive RNAs, RORA and KCTD16 modulate the aggressiveness of CoCl2-induced hypoxic osteosarcoma cells

Hypoxia is a defining feature of the solid tumour microenvironment and a major determinant of therapeutic response. Hypoxia-inducible factors (HIFs) are central regulators of transcriptional reprogramming under hypoxic stress. Hypoxia can paradoxically elicit both tumour-promoting and tumour-suppressive outcomes, suggesting regulatory mechanisms beyond canonical HIF-dependent pathways. Emerging evidence indicates that hypoxia-responsive RNAs (HRRs) may also be regulated independently of HIFs, with posttranscriptional stabilization playing a critical determinant of hypoxic adaptation. Cytoplasmic mRNA recapping mediated by the cytoplasmic capping enzyme (cCE) has recently emerged as an important post-transcriptional regulatory process, yet its role in hypoxia-driven RNA regulation remains poorly understood. Here, we aimed to identify novel HRRs that modulate cellular adaptability to hypoxia and to determine whether these transcripts are regulated by cCE. Using CoCl2-induced hypoxia, we observed a significant reduction in osteosarcoma cell aggressiveness, characterized by decreased proliferation, clonogenic survival, and migratory capacity. Transcriptomic profiling of hypoxic osteosarcoma cells identified RORA and KCTD16 as significantly upregulated and function as suppressors of tumour cell aggressiveness. Integrative in-silico CAGE tag analysis followed by cap-specific biochemical assays confirmed that both transcripts are post-transcriptionally stabilized by cCE. Mechanistically, hypoxia-induced stabilization of HIF1 transcriptionally elevated RORA and KCTD16 expression, while cCE further reinforced their stability post-transcriptionally. Stabilization of these cCE-targeted HRRs resulted in suppression of the oncogenic proliferation driver c-Myc, thereby attenuating the aggressive phenotype of hypoxic osteosarcoma cells. Collectively, our findings identify cCE as a previously unrecognized post-transcriptional regulator in hypoxia biology and reveal a RNA-centric mechanism by which hypoxia can restrain tumour aggressiveness.

molecular biology↗

bioRxiv2026

CDK12/13 inhibitor, CTX-439, suppresses tumor growth and potentiates BCL-2 family blockade

CDK12 and CDK13 (CDK12/13) regulate transcription by phosphorylating Serine 2 (S2) of the C-terminal domain of RNA polymerase II and have been proposed as therapeutic targets in cancer. Here we report the development of CTX-439, a novel, orally bioavailable, ATP-competitive small-molecule CDK12/13 inhibitor. CTX-439 specifically inhibits S2 phosphorylation and downregulates many genes including those involved in DNA damage repair, thereby exerting a profound anti-cancer effect in vitro and in vivo including breast cancer PDX models. A CRISPR activation screen identified BCL-2 and BCL-xL, anti-apoptotic BCL-2 family members, as genes that when upregulated confer resistance to CTX-439. Simultaneous inhibition of BCL-2/BCL-xL and CDK12/13 rapidly induced apoptosis and significantly suppressed xenograft tumor growth. Mechanistically, CTX-439 downregulates MCL1 protein levels through transcriptional readthrough, shifting cell survival dependency to BCL-2 and BCL-xL. Our study provides novel insights into the anti-tumor effect of CDK12/13 inhibition and proposes a new combination therapy strategy with anti-apoptotic BCL-2 family inhibitors, which may improve therapeutic outcomes in cancer treatment.

cancer biology↗

bioRxiv2026

Chromatin modifiers KMT2D, BAF, and p300 are required for de novo binding of transcription factors on enhancers

Transcription factors (TFs) bind to enhancers and recruit H3K4me1 methyltransferase KMT2D, chromatin remodeler BAF, and H3K27 acetyltransferase p300 to activate transcription. However, the role of chromatin modifiers in regulating de novo binding of TFs on enhancers remains unclear. Using a robust nuclear translocation system, we show that the muscle lineage-determining TF MyoD binds to chromatin pervasively within one hour, with half of induced MyoD binding sites co-occupied by KMT2D, BAF, and p300. On the majority of these MyoD+ enhancers, acute depletion of KMT2D or short-term inhibition of BAF or p300 enzymatic activity markedly reduces de novo binding of MyoD as well as that of KMT2D, BAF, and p300. On enhancers with intact MyoD binding despite these perturbations, we observe a cooperative recruitment among chromatin modifiers. Similar interdependent relationships are observed between the signal-dependent TF Glucocorticoid Receptor and KMT2D, BAF, and p300. Together, our findings show that chromatin modifiers are not only downstream effectors but also required for de novo binding of TFs on enhancers, refining a model of enhancer establishment as a process governed by functional cooperation rather than a strict hierarchy. Bullet pointsO_LIAcute KMT2D depletion disrupts de novo binding of MyoD, BAF, and p300 on enhancers. C_LIO_LIBAF and p300 enzymatic activities are required for de novo binding of MyoD, BAF, KMT2D, and p300 on enhancers. C_LIO_LICooperative binding of KMT2D, BAF, and p300 on MyoD+ enhancers. C_LIO_LIGR displays interdependencies with chromatin modifiers KMT2D, BAF, and p300 on enhancers. C_LI

molecular biology↗

bioRxiv2026

PDLP5 regulates aquaporin-mediated hydrogen peroxide transport in Arabidopsis

Aquaporins facilitate the diffusion of water and small neutral molecules, including hydrogen peroxide (H2O2). In Arabidopsis, plasma membrane intrinsic proteins (PIPs, members of aquaporins) mediate H2O2 transport; however, the regulatory mechanisms governing their activity are not fully understood. Here, we show that plasmodesmata-located protein 5 (PDLP5), a key regulator of plasmodesmal function, negatively regulates PIP-dependent H2O2 transport. PDLP5 forms complexes with PIPs, with its extracellular domain predicted to associate with the extracellular face of the channel. PDLP5 overexpression suppresses H2O2 uptake and confers reduced sensitivity to H2O2-induced root growth inhibition, whereas pdlp5 mutants display the opposite phenotype. We further identify PIP2;5 as a critical component of PDLP5-mediated regulation. These findings reveal an extracellular mechanism for modulating aquaporin function, expanding current models of channel regulation in plants.

plant biology↗

bioRxiv2026

Dietary Lees Supplementation Enhances Poultry Health Performance Through Gut Ecosystem Reprogramming

The search for sustainable alternatives to in-feed antibiotics has intensified with the global antimicrobial resistance crisis. While microbial by-products show potential, their mechanisms remain elusive. This study reveals that spent yeast lees, a fermentation by-product, profoundly reprograms the chicken gut ecosystem to enhance growth. We investigated the differential effects of live spent lees versus autoclaved spent lees from a molasses fermenter with Saccharomyces cerevisiae. In a 14-day controlled trial, 0-day-old poultry chicks (n=15) were assigned to a control diet (n=5), a live spent Lees-supplemented diet (n=5), or an autoclaved spent Lees-supplemented diet (n=5). Through the feeding trial with either live spent Lees or autoclaved spent Lees, we demonstrate significant enhancement of growth performance, with autoclaved spent Lees achieving the highest final body weight (573.4 {+/-} 17.2 g). Using deep shotgun metagenomic sequencing of faecal samples, we demonstrate that both spent Lees forms induced a dramatic ecological shift, driving the gut microbiome to a state of monodominance by Bacteroides fragilis (reaching 74.83% with live spent Lees). This was accompanied by the near-complete eradication of enteropathogens like like Enterococcus faecium and Escherichia coli. Crucially, live spent Lees supplementation effectively countered a natural age-dependent expansion of the gut resistome, eliminating the high-risk oxazolidinone resistance gene o23S and restructuring the virulome away from offensive effector systems. However, this beneficial restructuring came at the cost of significantly reduced microbial diversity and suppression of beneficial commensals. A key finding was that autoclaved spent Lees, while inducing a less extreme microbial shift, yielded superior final body weight, suggesting its lysed cells provide enhanced nutritional availability. Our work establishes spent yeast Lees not as mere waste, but as a potent, multi-functional supplement that enhances growth through gut ecosystem engineering, yet necessitates a strategic choice between its live and autoclaved forms based on production priorities.

microbiology↗

bioRxiv2025

AHA1 regulates Aβ production via modulation of APP expression and γ-secretase assembly

Deposition of amyloid {beta}-protein (A{beta}) is a hallmark of Alzheimers disease (AD), produced by {gamma}-secretase-mediated cleavage of amyloid precursor protein (APP). The 90-kDa heat shock protein (Hsp90) co-chaperone, activator of Hsp90 ATPase homolog 1 (AHA1), is known to promote the accumulation of toxic tau species; however, its effects on A{beta} production remain unclear. Here, we show that knockdown of endogenous AHA1 decreases A{beta} generation and reduces APP and {gamma}-secretase components, whereas AHA1 overexpression elevates A{beta} production and the expression of these proteins. The AHA1-E67K mutant, which has impaired Hsp90 binding, lowers A{beta} production and the levels of APP and {gamma}-secretase components compared with wild-type AHA1. AHA1 associates with APP and immature {gamma}-secretase components, including anterior pharynx-defective phenotype 1 (APH1), indicating its role in APP proteolysis and A{beta} production. Disruption of the AHA1/Hsp90 complex--through AHA1 knockdown, the E67K mutant, or a small-molecule inhibitor--reduces {gamma}-secretase assembly. Familial AD mutations in APP-C99 and presenilin-1 (PS1) increase AHA1, Hsp90, APP, and APH1 expression, enhancing A{beta} production. Importantly, AHA1 knockdown decreases abnormal A{beta} generation and C99, PS1-CTF, and APH1 levels in mutant APP cells, while AHA1 overexpression enhances A{beta} production in PS1 mutant cells. Collectively, these findings reveal that AHA1 regulates A{beta} production by modulating APP expression and {gamma}-secretase assembly, establishing AHA1 as a potential target for therapeutic intervention in AD.

neuroscience↗

bioRxiv2025

Motility-Driven Viscoelastic Control of Tissue Morphology in Presomitic Mesoderm

During development, embryonic tissues experience mechanical stresses ranging from cellular to supracellular length scales. In response, cells generate active forces that drive rearrangements, allowing the tissue to relax accumulated stresses. The nature of these responses depends strongly on the magnitude and duration of the deformation, giving rise to the tissues characteristic viscoelastic behavior. Although experiments have characterized tissue rheology in various contexts, simpler theoretical approaches that directly connect cellular activity to emergent rheological behavior are still limited. In this study, we employ a vertex-based model of epithelial tissue incorporating active force fluctuations in cell vertices to represent cell motility. We capture distinct rounding dynamics and motility-dependent timescales by benchmarking against experimental observations such as the bulging of presomitic mesoderm (PSM) explants driven by Fibroblast Growth Factor(FGF) gradients. Stress relaxation tests reveal rapid short-timescale relaxation alongside persistent longtimescale residual stresses that decrease from anterior to posterior (AP) region of the PSM. By applying oscillatory shear, we analyzed the resulting elastic and viscous responses, revealing motility dependence of storage and loss modulus. Finally, we introduce spatially patterned cues applied in a temporally pulsed manner, mimicking dynamic biochemical or mechanical signals during development. Our results show that while higher motility promotes tissue remodeling in response to these cues, this response is constrained by spatial scale; cellular-scale perturbations are relaxed irrespective of motility strength, preventing complete morphological adaptation.

developmental biology↗

bioRxiv2025

Efineptakin alfa (NT-I7) improves overall survival and induces tertiary lymphoid structures in murine lung tumors

Tertiary lymphoid structures (TLSs) are emerging as good predictive biomarkers of response to cancer immunotherapy. However, therapeutic strategies to induce these structures are currently limited. We evaluated the therapeutic benefit of efineptakin alfa (NT-I7), a long-acting form of IL-7, and its ability to induce TLSs in a murine lung tumor model. NT-I7 improved overall survival in tumor-bearing mice. It also increased the abundance of T, B, dendritic cells, and stem-like CD8 T cells and promoted the formation of immune aggregates in the tumor microenvironment (TME). Stem-like CD8 T cells were preferentially located in the immune aggregates. Spatial transcriptomic analyses of the TME further demonstrated that the immune aggregates induced by NT-I7 included TLSs with enrichment of Cd274 (PD-L1) transcripts and genes involved in antigen processing and presentation. Upregulation of Cd274 in the TLSs may provide opportunities for synergy between NT-I7 and PD-1-targeted immunotherapy. STATEMENT OF SIGNIFICANCEThis study demonstrates the ability of efineptakin alfa (NT-I7) to potentially augment the clinical efficacy of cancer immunotherapy by inducing tertiary lymphoid structures in the tumor microenvironment.

immunology↗

bioRxiv2025

Fear, anxiety, and the extended amygdala- Absence of evidence for strict functional segregation

Since the time of Freud, the distinction between fear and anxiety has been a hallmark of influential models of emotion and emotional illness, including the Diagnostic and Statistical Manual of Mental Disorders (DSM) and Research Domain Criteria (RDoC). Fear and anxiety disorders are common, debilitating, and challenging to treat, underscoring the importance of developing accurate models of the underlying neurobiology. Although there is consensus that the extended amygdala (EA) plays a central role in orchestrating responses to threat, the respective contributions of its two major subdivisions--the central nucleus of the amygdala (Ce) and bed nucleus of the stria terminalis (BST)--remain contentious. To help adjudicate this debate, we performed a harmonized mega-analysis of fMRI data acquired from 295 adults as they completed a well-established threat-anticipation paradigm. Contrary to popular double-dissociation models, results demonstrated that the Ce responds to temporally uncertain threat and the BST responds to certain threat. In direct comparisons, the two regions showed statistically indistinguishable responses, with strong Bayesian evidence of regional equivalence. In contrast, frontocortical regions responded preferentially to uncertain-threat anticipation. Together, these observations underscore the need to reformulate conceptual models that posit a strict segregation of temporally certain and uncertain threat processing in the EA.

neuroscience↗

bioRxiv2025

Missense3D-PTMdb an interactive web resource to explore and visualize genetic variants and post-translational modifications sites (PTMs) using AlphaFold 3D models

Only a fraction of the >11 million missense variants identified in the human population has a known damaging or tolerated clinical impact. Post-translational modifications (PTMs), such as phosphorylation, glycosylation and ubiquitination, are key regulators of protein function and structure, and are critical for protein localisation, stability and interactions with other molecules. The ability of a protein to undergo PTMs, is subject to a correctly folded protein structure, and the recognition and binding of enzymes to specific amino acid motifs in close proximity to residues that undergo PTMs [PTM residue]. AlphaFold models provide an unprecedented opportunity to perform sequence-structure mapping of variants, which are in close linear or spatial proximity to a PTM site and should have their impact on protein function experimentally investigated. We present Missense3D-PTMdb, a "one-stop-shop" interactive web tool that provides a user-friendly sequence-structure mapping of 20,235 human proteins to 11,544,303 naturally occurring human missense variants, 203,775 PTM sites and their neighbours in sequence and 3D structure space using AlphaFold generated 3D models of the human proteome. Additionally, the sequence-structure mapping tool allows visualization and exploration of any human variant not currently stored in the database. Missense3D-PTMDb is freely available at https://missense3d.bc.ic.ac.uk/ptmdb.

genetics↗

bioRxiv2025

Heightened subcortical reactivity to uncertain-threat is associated with future internalizing symptoms, conditional on stress exposure

BackgroundAnxiety, depression, and related internalizing illnesses are a leading burden on global public health, and often emerge during times of stress. Yet the underlying neurobiology has remained enigmatic, hindering treatment development. MethodsHere we used a combination of tools--including a well-established threat-anticipation fMRI paradigm and longitudinal assessments of internalizing symptoms and negative life events (NLEs)--to identify the neural systems associated with future internalizing illness in a risk-enriched sample of 224 emerging adults followed for 2.5 years. We performed parallel analyses in an overlapping sample of 209 participants who completed a popular threat-related faces paradigm. ResultsHere we show that heightened reactivity to uncertain-threat anticipation in the bed nucleus of the stria terminalis and the periaqueductal gray is associated with a worsening longitudinal course of broadband internalizing symptoms among individuals with low levels of NLE exposure. These associations were specific to uncertain threat and generally remained significant when controlling for concurrent measures of threat-elicited distress or psychophysiological arousal, highlighting the added value of the neuroimaging measures. Symptom trajectories were unrelated to amygdala and frontocortical reactivity to anticipated threat. Contrary to past research, amygdala reactivity to threat-related faces was unrelated to future symptoms. ConclusionsThese observations provide a novel neurobiological framework for conceptualizing transdiagnostic internalizing risk and lay the groundwork for mechanistic and therapeutics research. A racially diverse, risk-enriched sample and pre-registered, best-practices approach enhance confidence in the robustness and translational relevance of these results.

neuroscience↗

bioRxiv2025

Biochemical engineering of 5hmdC-DNA using a Tet3 double-mutant

5-Hydroxymethyl-2-deoxycytidine (5hmdC) is an important epigenetic marker involved in gene regulation and DNA demethylation. It has potential use as a biomarker for cancer and other diseases due to its significant depletion in various cancers and disease models. This research aimed to develop a reliable and efficient method for generating 5hmdC-containing DNA, addressing limitations in existing techniques. We created a Tet3 stalling mutant that converts 5-methyl-2'-deoxycytidine (5mdC) into a mixture of 5hmdC and 5-formyl-2'-deoxycytidine (5fdC), followed by a reduction step to convert 5fdC to 5hmdC, ensuring a pure 5hmdC state within the CpG context. This method can convert any PCR product, synthetic oligos, and entire genomes into 5hmdC-modified DNA. The principal results demonstrate high specificity and efficiency, providing a robust tool for epigenetic research, cancer diagnostics, and protein binding assays. Additionally, our technique offers 5hmdC-DNA for functional studies and as standards for diagnostic assays.

biochemistry↗

bioRxiv2025

Associations between floor material and E. coli contamination in rural Bangladeshi households

Soil floors are common in low-income countries and can harbor contamination from unsafely managed human and animal fecal waste. Soil/dust ingestion directly from floors or indirectly via hands, drinking water and food can significantly contribute to childrens ingestion of fecal organisms. We assessed if finished (e.g., concrete) floors are associated with lower E. coli contamination in the domestic environment in rural Bangladesh. We collected samples from 1864 households over 3.5 years, including stored drinking water, child and caregiver hand rinses, courtyard soil, food, and flies (n=24,118 samples), and enumerated E. coli using IDEXX Quanti-Tray/2000. Controlling for potential confounders (socio-demographics, water/sanitation status, animal ownership), households with finished floors had slightly lower log10-transformed E. coli counts ({Delta}log10= -0.10 (-0.20, 0.00)) and prevalence (prevalence ratio=0.90 (0.83, 0.98)) on child hands than households with soil floors; floor material was not associated with contamination levels in other sample types. Finished floors were associated with lower E. coli contamination of child hands, food and stored drinking water following periods of higher rainfall and temperature, and lower E. coli contamination of child hands in households with more domestic animals. Measures to control enteric infections in low-income countries should test flooring improvements to reduce exposure to fecal contamination.

microbiology↗

bioRxiv2025

Structural analyses of gibberellin-mediated DELLA protein degradation

Gibberellin promotes plant growth by downregulating growth-repressor DELLA proteins. The gibberellin receptor GID1 binds to DELLA proteins in the presence of gibberellin, triggering their degradation through polyubiquitination by SCFSLY1/GID2 ubiquitin E3 ligase. Despite extensive studies, the molecular mechanisms by which DELLA proteins assemble with SCFSLY1/GID2 to regulate plant growth remain poorly understood. Here, we present two cryo-electron microscopy structures of the Arabidopsis thaliana DELLA protein RGA in complex with GID1A and GID1A-SLY1-ASK2, respectively. Structural analysis revealed that RGA interacts with GID1A and SLY1 through non-overlapping binding surfaces, stabilizing the proteins. This suggests that the SCFSLY1-RGA-GID1A complex assembles through stepwise stabilization induced by gibberellin. Furthermore, the structures indicate that RGA does not interact with IDD family transcription factors when bound to SLY1, suggesting that the binding of DELLA proteins to GID1/SLY1 and transcription factors is mutually exclusive. These findings provide insights into how DELLA proteins regulate transcription factor activity in response to gibberellin.

plant biology↗

bioRxiv2024

Evolvability through segmental duplication follows species-specific dynamics

Segmental duplications are major drivers of evolutionary innovation, yet their dynamics across vertebrates remain poorly understood. Here, we identify segmental duplications from long-read sequenced genomes of 117 vertebrates and the starfish, generating the largest multi-species dataset of its kind. We find that vertebrate genomes show a higher propensity for tandem duplications than for interspersed duplications. However, when focusing only on subtelomeric regions, avian and mammalian genomes show the opposite propensity toward interspersed duplications. We also observe that, across vertebrates, tandem duplications tend to be larger than interspersed duplications. Next, we construct a segmental duplication network for each species, and use network-derived properties to quantify the duplication landscape for that species. Functional enrichment analysis of hyper-duplicated genes reveals a strong enrichment in platypus for pheromone response, driven by the expansion of the vomeronasal pheromone receptor V1R gene family. Overall, our results uncover the general properties of vertebrate segmental duplication, demonstrate the rapid evolution of segmental duplication landscapes, and highlight the utility of network-based approaches for studying genome evolution. SignificanceGene and regulatory region duplications are a fundamental source of evolutionary raw material. Here we generate segmental duplication calls from 117 vertebrate species. We find that vertebrate genomes have a bias towards tandem duplications relative to interspersed duplications. However, in the subtelomeric regions, birds and mammals exhibit an opposite bias toward interspersed duplications. Our analysis of segmental duplication networks demonstrate that duplication landscapes evolve rapidly, following species-specific rather than phylogenetic patterns. These findings indicate that the genomic architecture underlying segmental duplications is highly dynamic, uniquely shaping each lineages potential to adapt. Our study provides the most comprehensive view of vertebrate segmental duplications to date and establishes a network-based framework for studying genomic structural evolution.

evolutionary biology↗