Biology subjects

Gutierrez-Marcos, J.

Publications and source records attributed to Gutierrez-Marcos, J..

12 recordsLinked to original sources

bioRxiv2025

Quantitative mapping of antigen specificity in adaptive immune repertoire embedding spaces

The adaptive immune receptor repertoire (AIRR) encompasses an immense diversity of antibody and T-cell receptor sequences, whose collective organization - how receptors are distributed, clustered, and interrelated across sequence and functional (e.g., antigen-binding) dimensions - remains poorly characterized. Representing AIRRs in continuous representation spaces that capture sequence, biochemical, and structural similarity between receptors may enable comparisons beyond discrete sequence features. Using both one-hot encodings and protein language model (PLM) embeddings, we developed a quantitative framework to map immune receptor organization at global (sequence-set-level) and local (single-sequence-level) scales. Applying the geometry-aware Wasserstein-2 distance, we show that the global structure of the AIRR space can be recovered from as few as [~]105 sequence embeddings, at least 10 orders of magnitude smaller than the theoretical immune receptor diversity. We found that immune receptor sequences annotated with different antigen specificities occupy distinct regions of representation space. To resolve local relationships, we introduce a spatial homogeneity metric that quantifies the extent of functional clustering. We found higher spatial homogeneity in embedding spaces than in sequence space for diverse antigen-specific datasets. Our framework establishes a foundation for quantitative mapping of adaptive immune repertoire organization.

immunology↗

bioRxiv2025

Molecular characterization of capulet2 reveals the importance of ANAPHASE PROMOTING COMPLEX 6 maternal expression in endosperm development

Flowering plants are characterized by a double fertilization event, and the fertilized female gametes develop into the endosperm and embryo. Genomic imprinting promotes parental allele-specific gene expression in the endosperm by epigenetic modifications such as DNA methylation. Similarly, gametophyte maternal effects influence gene function in the female gametophyte that affects development of the endosperm and embryo post-fertilization. While most imprinted genes do not display a seed phenotype upon mutation, gametophyte maternal effect mutants are characterized by distorted seed development upon maternal transmission of the mutant allele. Here, we have investigated the gametophyte maternal effect mutant capulet2 (cap2). We have established CAP2 to be encoded by ANAPHASE PROMOTING COMPLEX 6 (APC6), a subunit of the anaphase promoting complex/cyclosome (APC/C). Investigation of further cap2/apc6 alleles revealed female gametophyte maternal effects both in mutant segregation and seed phenotype, and both cap2 and apc6 phenotypes were rescued by an APC6 transgene. Furthermore, we demonstrate that APC6 is a maternally expressed imprinted gene, in line with the observed female gametophyte maternal effect phenotype. To this end, we observed irregular nuclear division of the endosperm coenocyte in cap2/apc6 mutants, suggesting a role for the APC/C in early endosperm development. We further demonstrate that similar endosperm defects are also produced by mutation of APC1, another subunit of the APC/C. Similar to cap2/apc6, APC1 is imprinted and only expressed from the maternal allele, suggesting a maternal bias in the control of APC/C in the developing endosperm.

developmental biology↗

bioRxiv2023

Cartography of the developability landscapes of native and human-engineered antibodies

Designing effective monoclonal antibody (mAb) therapeutics faces a multi-parameter optimization challenge known as "developability", which reflects an antibodys ability to progress through development stages based on its physicochemical properties. While natural antibodies may provide valuable guidance for mAb selection, we lack a comprehensive understanding of natural developability parameter (DP) plasticity (redundancy, predictability, sensitivity) and how the DP landscapes of human-engineered and natural antibodies relate to one another. These gaps hinder fundamental developability profile cartography. To chart natural and engineered DP landscapes, we computed 40 sequence- and 46 structure-based DPs of over two million native and human-engineered single-chain antibody sequences. We found lower redundancy among structure-based compared to sequence-based DPs. Sequence DP sensitivity to single amino acid substitutions varied by antibody region and DP, and structure DP values varied across the conformational ensemble of antibody structures. Sequence DPs were more predictable than structure-based ones across different machine-learning tasks and embeddings, indicating a constrained sequence-based design space. Human-engineered antibodies were localized within the developability and sequence landscapes of natural antibodies, suggesting that human-engineered antibodies explore mere subspaces of the natural one. Our work quantifies the plasticity of antibody developability, providing a fundamental resource for multi-parameter therapeutic mAb design.

bioinformatics↗

bioRxiv2023

Atypical memory B cells form a pre-plasmacellular reservoir for steady-state IgD responses to common nasopharyngeal antigens

The human nasopharyngeal mucosa includes organized lymphoepithelial structures continually engaged in frontline immune responses to aerodigestive antigens. Advancing our understanding of these responses might lead to the development of new strategies for the prevention and treatment of common immune disorders such as allergies. Here we identified a hitherto elusive tonsillar subset of atypical IgD class-switched IgD+IgM- memory (IgD-ME) B cells that were clonally related to IgD+IgM- germinal center (IgD-GC) B cells and IgD-secreting IgD+IgM- plasma cells (IgD-PCs) but not anergic IgD+IgM- B cells. Consistent with their pre-plasmacellular properties, IgD-ME B cells served as preferential precursors of IgD-PCs over IgD-GC B cells. IgD antibodies from IgD+IgM- cells acquired reactivity to multiple oral, airborne and commensal antigens through a mutation-dependent pathway involving both innate and adaptive signals. Thus, IgD-ME B cells may form a ready-to-use pre-plasmacellular reservoir for steady-state IgD responses likely aimed at enhancing nasopharyngeal homeostasis. One Sentence SummaryTonsillar atypical memory B cells form a ready-to-use pre-plasmacellular repertoire for IgD responses to common aerodigestive antigens.

immunology↗

bioRxiv2023

Long noncoding RNA-mediated epigenetic regulation of auxin-related genes controlling shade avoidance syndrome in Arabidopsis thaliana

The long noncoding RNA (lncRNA) AUXIN-REGULATED PROMOTER LOOP (APOLO) recognizes a subset of target loci across the Arabidopsis thaliana genome by forming RNA-DNA hybrids (R-loop) and modulating local three-dimensional chromatin conformation. Here we show that APOLO is involved in regulating the shade avoidance syndrome (SAS) by dynamically modulating the expression of key factors. In response to far-red (FR) light, the expression of APOLO anticorrelates with its target BRANCHED1 (BRC1), a master regulator of shoot branching in Arabidopsis thaliana. APOLO deregulation results in BRC1 transcriptional repression and an increase in the number of branches. APOLO transcriptional accumulation fine-tunes the formation of a repressive chromatin loop encompassing the BRC1 promoter, which normally occurs only in leaves as well as in a late response to FR treatment in axillary buds. In addition, our data reveal that APOLO participates in leaf hyponasty, in agreement with its previously reported role in the control of auxin homeostasis through direct modulation of YUCCA2 (auxin synthesis), PID and WAG2 (auxin efflux). We found that direct application of APOLO RNA to leaves results in a rapid increase in auxin accumulation that is associated with changes in the response of the plants to FR light. Collectively, our data support the view that lncRNAs coordinate the shade avoidance syndrome in Arabidopsis thaliana and shed light on the potential of lncRNAs as bioactive exogenous molecules. Deploying exogenous RNAs that modulate plant-environment interactions are important new tools for sustainable agriculture.

plant biology↗

bioRxiv2022

Predictable and stable epimutations induced during clonal propagation with embryonic transcription factors

Although clonal propagation is frequently used in commercial plant breeding and plant biotechnology programs because it minimizes genetic variation, it is not uncommon to observe clonal plants with stable phenotypic changes, a phenomenon known as somaclonal variation. Several studies have shown that epigenetic modifications induced during regeneration are associated with this newly acquired phenotypic variation. However, the factors that determine the extent of somaclonal variation and the molecular changes associated with it remain poorly understood. To address this gap in our knowledge, we compared clonally propagated Arabidopsis thaliana plants derived from somatic embryogenesis using two different embryonic transcription factors-RWP-RK DOMAIN-CONTAINING 4 (RKD4) or LEAFY COTYLEDON2 (LEC2) and from two epigenetically distinct tissues. We found that both the epi(genetic) status of explant and the regeneration protocol employed play critical roles in shaping the molecular and phenotypic state of clonal plants. Phenotypic variation of regenerated plants can be largely explained by the inheritance of tissue-specific DNA methylation imprints, which are associated with specific transcriptional and metabolic changes in sexual progeny of clonal plants. Moreover, regenerants from roots were particularly affected by the inheritance of epigenetic imprints, which resulted in increased accumulation of salicylic acid in leaves and accelerated plant senescence. Collectively, our data reveal pathways for targeted manipulation of phenotypic variation in clonal plants.

plant biology↗

bioRxiv2021

Individualized VDJ recombination predisposes the available Ig sequence space

The process of recombination between variable (V), diversity (D), and joining (J) immunoglobulin (Ig) gene segments determines an individuals naive Ig repertoire, and consequently (auto)antigen recognition. VDJ recombination follows probabilistic rules that can be modeled statistically. So far, it remains unknown whether VDJ recombination rules differ between individuals. If these rules differed, identical (auto)antigen-specific Ig sequences would be generated with individual-specific probabilities, signifying that the available Ig sequence space is individual-specific. We devised a sensitivity-tested distance measure that enables inter-individual comparison of VDJ recombination models. We discovered, accounting for several sources of noise as well as allelic variation in Ig sequencing data, that not only unrelated individuals but also human monozygotic twins and even inbred mice possess statistically distinguishable immunoglobulin recombination models. This suggests that, in addition to genetic, there is also non-genetic modulation of VDJ recombination. We demonstrate that population-wide individualized VDJ recombination can result in orders of magnitude of difference in the probability to generate (auto)antigen-specific Ig sequences. Our findings have implications for immune receptor-based individualized medicine approaches relevant to vaccination, infection, and autoimmunity.

immunology↗

bioRxiv2020

A transposon surveillance mechanism that safeguards plant male fertility during stress

Although plants are able to withstand a range of environmental conditions, spikes in ambient temperature can impact plant fertility causing reductions in seed yield and significant economic losses1,2. Therefore, understanding the precise molecular mechanisms that underpin plant fertility under environmental constraints is critical to safeguard future food production3. Here, we identified two Argonaute-like proteins whose activities are required to sustain male fertility in maize plants under high temperatures. We found that MALE-ASSOCIATED ARGONAUTE 1 and 2 (MAGO1 and MAGO2) associate with temperature-induced phased secondary small RNAs in pre-meiotic anthers and are essential to control the activity of retrotransposons in male meiocyte initials. Biochemical and structural analyses revealed how MAGO2 activity and its interaction with retrotransposon RNA targets are modulated through the dynamic phosphorylation of a set of highly conserved surface-located serine residues. Our results demonstrate that an Argonaute-dependent RNA-guided surveillance mechanism is critical in plants to sustain male fertility under environmentally constrained conditions by controlling the mutagenic activity of transposons in male germ cells.

plant biology↗

bioRxiv2020

A new role for histone demethylases in the maintenance of plant genome integrity

Histone modifications deposited by the Polycomb repressive complex 2 (PRC2) play a critical role in the control of growth, development and adaptation to environmental fluctuations in most multicellular eukaryotes. The catalytic activity of PRC2 is counteracted by Jumonji-type (JMJ) histone demethylases, which shapes the genomic distribution of H3K27me3. Here, we show that two JMJ histone demethylases in Arabidopsis, EARLY FLOWERING 6 (ELF6) and RELATIVE OF EARLY FLOWERING 6 (REF6), play distinct roles in H3K27me3 and H3K27me1 homeostasis. We show that failure to reset these chromatin marks during sexual reproduction results in the inheritance of epigenetic imprints, which cause a loss of DNA methylation at heterochromatic loci and transposon activation. Thus, Jumonji-type histone demethylases in plants contribute towards maintaining distinct transcriptional states during development and help safeguard genome integrity following sexual reproduction.

plant biology↗

bioRxiv2019

Two Receptor-Like Kinases Required For Arabidopsis Endodermal Root Organisation Shape The Rhizosphere Microbiome

The Casparian Strip (CS) constitutes a physical diffusion barrier to water and nutrients in plant roots, and is formed by the polar deposition of lignin polymer in the endodermis. This precise pattern of lignin deposition is thought to be mediated by the scaffolding activity of membrane-bound Casparian Strip domain proteins (CASPs). However, we show that endodermis-specific receptor-like kinase 1 (ERK1) and ROP Binding Kinase1 (RBK1) are also involved in this intricate process, with the former playing an essential role both in the localization of CASP1 and in lignin deposition. We further characterised ERK1 and determined its subcellular localisation in the cytoplasm and nucleus of the endodermis, as well as provide evidence for its involvement in a signalling pathway together with the circadian clock regulator, Time for Coffee (TIC). We also show that disruption to CS organisation and increased suberisation in the endodermis due to loss of function of either ERK1 or TIC collectively leads to an altered root microbiome composition. Thus, our work reveals additional players in the complex cascade of signalling events operating in the root endodermis to establish both the CS diffusion barrier and the microbial composition of the rhizosphere.

plant biology↗

bioRxiv2019

Importance of parental genome balance in the generation of novel yet heritable epigenetic and transcriptional states during doubled haploid breeding

BackgroundDoubling the genome contribution of haploid plants has accelerated breeding in most cultivated crop species. Although plant doubled haploids are isogenic in nature, they frequently display unpredictable phenotypes, thus limiting the potential of this technology. Therefore, being able to predict the factors implicated in this phenotypic variability could accelerate the generation of desirable genomic combinations and ultimately plant breeding.\n\nResultsWe use computational analysis to assess the transcriptional and epigenetic dynamics taking place during doubled haploids generation in the genome of Brassica oleracea. We observe that doubled haploid lines display unexpected levels of transcriptional and epigenetic variation, and that this variation is largely due to imbalanced contribution of parental genomes. We reveal that epigenetic modification of transposon-related sequences during DH breeding contributes to the generation of unpredictable yet heritable transcriptional states. Targeted epigenetic manipulation of these elements using dCas9-hsTET3 confirms their role in transcriptional regulation. We have uncovered a hitherto unknown role for parental genome balance in the transcriptional and epigenetic stability of doubled haploids.\n\nConclusionsThis is the first study that demonstrates the importance of parental genome balance in the transcriptional and epigenetic stability of doubled haploids, thus enabling predictive models to improve doubled haploid-assisted plant breeding.

plant biology↗

bioRxiv2018

Incomplete reprogramming of cell-specific epigenetic marks during asexual reproduction leads to heritable phenotypic variation in plants

Plants differ from animals in their capability to easily regenerate fertile adult individuals from terminally differentiated cells [1]. This unique developmental plasticity is commonly observed in nature where many species can reproduce asexually through the ectopic initiation of organogenic or embryogenic developmental programs [2, 3]. However, it is not currently known if this developmental reprogramming is coupled to a global epigenomic resetting, or what impact it has on the phenotype of the clonal progeny. Here we show that plants asexually propagated via induction of a zygotic developmental program do not fully reset cell-specific epigenetic imprints. These imprints are instead inherited even over multiple rounds of sexual reproduction, becoming fixed in hybrids and resulting in heritable molecular and physiological phenotypes that depend on the founder cell used. Our results demonstrate how novel phenotypic variation in plants can be unlocked through the incomplete reprogramming of cell-specific epigenetic marks during asexual propagation.

plant biology↗