Biology subjects

Permanyer, J.

Publications and source records attributed to Permanyer, J..

9 recordsLinked to original sources

bioRxiv2026

Evolutionary landscapes of zygotic genome activation across animals

During early animal embryogenesis, gene expression control shifts from maternally deposited products to newly transcribed RNA through zygotic genome activation (ZGA). Although essential and universal, ZGA remains poorly understood outside a few model species. Here, we generated a transcriptomic atlas of early embryogenesis across 61 animal species from 13 phyla and used a unified computational framework to infer ZGA timing systematically. We find extensive variation in ZGA onset across animals, but show that the ratio between genome size and egg cytoplasmic volume, a proxy for the nuclear-to-cytoplasmic ratio, robustly predicts when genome activation begins. We also reveal that zygotic genes also differ from maternal transcripts in genomic architecture, function and evolutionary conservation, suggesting that ZGA follows a conserved molecular logic despite flexible transcriptomic outputs.

evolutionary biology↗

bioRxiv2025

Neural microexons modulate arousal states via cAMP signalling in zebrafish

Arousal states, often dysregulated in neurodevelopmental disorders, shape how organisms perceive and respond to their environment. Here, we show that srrm3, a master regulator of neural microexons, is essential for normal arousal in zebrafish larvae. srrm3 mutants exhibit persistent hyperarousal, including sleep loss, sensory hypersensitivity, anxiety-like behaviour, and heightened neural and behavioural activity. Elevated cAMP signalling likely drives this hyperarousal, as pharmacologically reducing cAMP rescues mutant behaviour, while increasing cAMP in wild-type larvae phenocopies the mutant hyperaroused state. Pharmacological cAMP modulation also mimics and reverses srrm3-dependent transcriptional changes. These include immediate early gene downregulation, which, together with altered activity-dependent transcription factor motif occupancy, suggest adaptation to sustained neuronal hyperactivity. Additionally, srrm3 mutants show upregulation of microexon- containing genes, likely compensating for microexon loss. Together, these findings reveal a role for neural microexons in shaping arousal via cAMP signalling, providing insight into how splicing defects may underlie sensory and sleep disturbances.

neuroscience↗

bioRxiv2024

Phenotypic impact of individual conserved neuronal microexons and their master regulators in zebrafish

Microexons exhibit striking evolutionary conservation and are subject to precise, switch-like regulation in neurons, orchestrated by the splicing factors Srrm3 and Srrm4. Disruption of these regulators in mice leads to severe neurological phenotypes, and their misregulation is linked to human disease. However, the specific microexons involved in these phenotypes and the effects of individual microexon deletions on neurodevelopment, physiology, and behavior remain poorly understood. To explore this, we generated zebrafish lines with deletions of 18 individual microexons, alongside srrm3 and srrm4 mutant lines, and conducted comprehensive phenotypic analyses. We discovered that while loss of srrm3, alone or together with srrm4, resulted in significant alterations in neuritogenesis, locomotion, and social behavior, individual microexon deletions typically produced mild or no noticeable effects. Nonetheless, we identified specific microexons associated with defects in neuritogenesis (evi5b, vav2, itsn1, src) and social behavior (vti1a, kif1b). Additionally, most microexon deletions triggered coordinated transcriptomic changes in neural pathways, suggesting the presence of molecular compensatory mechanisms. Our findings suggest that the severe phenotypes caused by Srrm3/4 depletion arise from the combined effects of multiple subtle disruptions across various cellular pathways, which are individually well-tolerated.

molecular biology↗

bioRxiv2023

A novel regulatory mechanism of actin cytoskeleton dynamics through a neural microexon in DAAM1 is necessary for memory formation

Actin cytoskeleton dynamics is critical for nervous system development and function, yet the role of alternative splicing in controlling these processes is poorly understood. A highly conserved subset of neuronal-specific microexons coordinates fundamental aspects of nervous system biology. A subset of these exons is enriched in genes involved in actin cytoskeleton, yet their functions are unknown. Here, we focus on a microexon in DAAM1, a member of the formin-homology-2 (FH2) domain class of proteins, which have diverse functions associated with the reorganization of the actin cytoskeleton. Remarkably, splicing of the microexon extends the linker region of the DAAM1 FH2 domain and leads to qualitative and quantitative changes in actin polymerization. Deletion of the microexon results in neuritogenesis defects and increased calcium influx in differentiated neurons. Moreover, mice harboring the deletion exhibit postsynaptic defects, reduced number of immature dendritic spines, impaired long-term potentiation, and deficits in memory formation. These deficits are associated with increased RHOA/ROCK signaling, pivotal in controlling actin-cytoskeleton dynamics, and were rescued by treatment with a ROCK inhibitor. We thus demonstrate that a conserved neuronal microexon in DAAM1 is critical for controlling actin dynamics through the RHOA/ROCK signaling pathway and is necessary for normal cognitive functioning.

neuroscience↗

bioRxiv2022

Pervasive evolution of tissue-specificity of ancestral genes differentially shaped vertebrates and insects

Regulation of gene expression is arguably the main mechanism contributing to tissue phenotypic diversity within and between species. Here, we assembled an extensive transcriptomic dataset covering twenty bilaterian species and eight tissues, selecting a specular phylogeny that allowed both the combined and parallel investigation of gene expression evolution between vertebrates and insects. We specifically focused on widely conserved ancestral genes, identifying strong cores of pan-bilaterian tissue-specific genes and even larger groups that diverged to define vertebrate and insect tissues. Systematic inferences of tissue-specificity gains and losses show that nearly half of all ancestral genes have been recruited into tissue-specific transcriptomes. This occurred during both ancient and, especially, recent bilaterian evolution, with several gains being associated with the emergence of unique phenotypes. Such pervasive evolution of tissue-specificity was linked to gene duplication coupled with specialization, including an unappreciated prolonged effect of whole genome duplications during recent vertebrate evolution.

genomics↗

bioRxiv2021

The X-linked splicing regulator MBNL3 has been co-opted to restrict placental growth in eutherians

The eutherian placenta is a major site for parental genetic conflict. Here, we identify the X-linked Mbnl3 gene as a novel player in this dispute. Mbnl3 belongs to an RNA binding protein family whose members regulate alternative splicing and other aspects of RNA metabolism in association with cellular differentiation. We find that, in eutherians, Mbnl3 has become specifically expressed in placenta and has undergone accelerated sequence evolution leading to changes in its RNA binding specificities. Although its molecular roles are partly redundant with those of Mbnl2, Mbnl3 has also acquired novel biological functions. In particular, whereas Mbnl2;Mbnl3 double knockout mice display severe placental maturation defects leading to strong histological and functional abnormalities, Mbnl3 knockout alone results in increased placental growth and favors placental and fetal resource allocation during limiting conditions.

evolutionary biology↗

bioRxiv2021

Specialization of the photoreceptor transcriptome by Srrm3-dependent microexons is required for outer segment maintenance and vision

Retinal photoreceptors differ in their transcriptomic profiles from other neuronal subtypes, likely as a reflection of their unique cellular morphology and function in the detection of light thorough the ciliary outer segment. We discovered a new layer of this molecular specialization by revealing that the vertebrate retina expresses the largest number of tissue-enriched microexons of all tissue types. A subset of these microexons is included exclusively in photoreceptor transcripts, particularly in genes involved in cilia biogenesis and in vesicle-mediated transport. This microexon program is regulated by Srrm3, a paralog of the neural microexon regulator Srrm4. Despite both proteins positively regulate retina microexons in vitro, only Srrm3 is highly expressed in mature photoreceptors and its deletion in zebrafish results in widespread downregulation of microexon inclusion, severe photoreceptor alterations and blindness. These results shed light into photoreceptors transcriptomic specialization and functionality, uncovering new cell type-specific roles for Srrm3 and microexons with implication for retinal diseases.

systems biology↗

bioRxiv2021

Environmental enrichment induces epigenomic and genome organization changes relevant for cognitive function

In early development, the environment triggers mnemonic epigenomic programs resulting in memory and learning experiences to confer cognitive phenotypes into adulthood. To uncover how environmental stimulation impacts the epigenome and genome organization, we used the paradigm of environmental enrichment (EE) in young mice constantly receiving novel stimulation. We profiled epigenome and chromatin architecture in whole cortex and sorted neurons by deep-sequencing techniques. Specifically, we studied chromatin accessibility, gene and protein regulation, and 3D genome conformation, combined with predicted enhancer and chromatin interactions. We identified increased chromatin accessibility, transcription factor binding including CTCF-mediated insulation, differential occupancy of H3K36me3 and H3K79me2, and changes in transcriptional programs required for neuronal development. EE stimuli led to local genome re-organization by inducing increased contacts between chromosomes 7 and 17 (inter-chromosomal). Our findings support the notion that EE-induced learning and memory processes are directly associated with the epigenome and genome organization. Highlights- Environmental enrichment (EE) alters chromatin conformation, CTCF binding, and spatially 3D genome changes, thereby regulating cognitive function during the first steps of life after birth. - Transcription-associated gene body marks H3K79me2 and H3K36me3 are differently influenced by EE in cortical brain cells and binding is exacerbated upon stimulation in an age-dependent manner. - EE-induced changes of 3D genome organization increase inter-chromosomal interactions of genes associated with synaptic transmission and AMPA receptor genes on chromosomes 7 and 17.

neuroscience↗

bioRxiv2020

ACME dissociation: a versatile cell fixation-dissociation method for single-cell transcriptomics

Single-cell sequencing technologies are revolutionizing biology, but are limited by the need to dissociate fresh samples that can only be fixed at later stages. We present ACME (ACetic-MEthanol) dissociation, a cell dissociation approach that fixes cells as they are being dissociated. ACME-dissociated cells have high RNA integrity, can be cryopreserved multiple times, can be sorted by Fluorescence-Activated Cell Sorting (FACS) and are permeable, enabling combinatorial single-cell transcriptomic approaches. As a proof of principle, we have performed SPLiT-seq with ACME cells to obtain around ∼34K single cell transcriptomes from two planarian species and identified all previously described cell types in similar proportions. ACME is based on affordable reagents, can be done in most laboratories and even in the field, and thus will accelerate our knowledge of cell types across the tree of life.Competing Interest StatementThe authors have declared no competing interest.View Full Text

systems biology↗