Javier Jurado-Aguilar 1 2 3 4 , Emma Barroso 1 2 3 4 , Patricia Rada 3 5 , Mona Peyman 1 2 3 4 , Adel Rostami 1 2 3 4 , Jesús Balsinde 3 6 , Ángela M Valverde 3 5 , Walter Wahli 7 8 , Xavier Palomer 1 2 3 4 , Manuel Vázquez-Carrera 9 10 11 12
Affiliations
Greta Skrupskelyte 1 , Joanna C Fowler 2 , Stefan Dentro 2 3 4 , Carine Winkler 5 , Irina Abnizova 2 , Niklaus Beumer 3 6 7 , Roshan Sood 2 , Thomas Quarrell 8 , Charlotte King 2 , Jivko Kamarashev 9 , Emmanuella Guenova 10 11 , Moritz Gerstung 3 4 , Benjamin A Hall 12 , Liliane Michalik 5 , Philip H Jones 13 14
Identifying the mutant genes that are selected during carcinogenesis is key to identifying candidates for intervention and understanding the processes that promote transformation. Here we applied two selection metrics to study the dynamics of mutational selection in a mouse model of ultraviolet light driven skin carcinogenesis in which multiple synchronous tumors develop in each animal. Sequencing normal skin and tumors over a time course revealed two genetic routes to squamous carcinoma. Nonsynonymous Trp53 mutants were positively selected in both epidermis and tumors and present in 90% of tumors. The remaining tumors carried other oncogenic mutants, including activating Kras mutations. However, other positively selected mutant genes lost their competitive advantage in heavily mutated epidermis and in tumors. We found ten mutant genes under negative selection in normal skin, one of which was also negatively selected in tumors. In addition one gene was negatively selected in tumors but not normal skin. We conclude that analysing selection in normal tissue alongside tumors may resolve the dynamics of selection in carcinogenesis and refine the identification of cancer drivers.
Monogenic expression of odorant receptors (ORs) in individual sensory neurons is a hallmark of olfactory systems in insects and vertebrates. New studies highlight how transcriptional interference and antisense transcription might ensure such selectivity in large OR arrays of social insects.
Franz Müller 1 , Sonja Neuser 2 , Gaurav Shrestha 3 , Netra P Neupane 4 , Katharina J Götze 1 , Nicola Brunetti-Pierri 5 6 7 , Gaetano Terrone 5 , Alexandre Reymond 8 , Koen L van Gassen 9 , Eva Brilstra 9 , Katharina Steindl 10 , Anais Begemann 10 , Anita Rauch 10 , Jonathan Rips 11 , Duha Fahham 11 , Tahsin Stefan Barakat 12 , Olivier Patat 13 , Jérémie Mortreux 14 , Matthew Hoi Kin Chau 15 16 17 , Jill A Rosenfeld 18 , Elizabeth Mizerik 18 19 , Swati Srivastava 18 20 , Xi Luo 18 20 , Anne-Kristin Dahse 1 , Nicole Scholz 1 , Joydip Das 4 , Gregg Roman 21 , Tobias Langenhan 1 22 23 , Rami Abou Jamra 2 , Achmed Mrestani 1 24 , Dmitrij Ljaschenko 1
Affiliations
UNC13s are presynaptic proteins essential for neurotransmitter release at chemical synapses. In this study, we present eleven patients from nine families with severe neurodevelopmental impairments, who carry rare, biallelic UNC13C single-nucleotide variants (SNVs). Six missense variants, each identified in compound heterozygosity in one of three of these patients, were introduced into the Drosophila melanogaster ortholog unc13 using a previously established CRISPR/Cas9-based method for rapid and scarless genomic modifications, hypothesising that they underlie the observed clinical manifestations. However, none of the introduced mutations influenced Mendelian ratios, negative geotaxis, or lifespan of the fruit flies. Interestingly, two variants located outside the gene regions encoding known UNC13C domains caused a decreased ethanol sensitivity in Drosophila, while the Thr1729Met substitution within the C1 domain resulted in increased ethanol sensitivity. Molecular dynamics simulations of the latter mutant gene product suggested that the altered protein conformation enhances exposure of the ethanol-binding site, thereby increasing sensitivity to ethanol. These findings reinforce previous evidence highlighting the critical role of the C1 domain in ethanol sensitivity. Given the involvement of the C1 domain in synaptic plasticity this result might implicate an influence of the Thr1729Met on synaptic function.
Keywords: Chemical synapse; Dunc13; Ethanol sensitivity; Molecular dynamics simulation; Neurodevelopmental disease; UNC13C; Unc13.
© 2025 The Authors.
Paulišić S, Boccaccini A, Dreos R, Ambrosini G, Guex N, Benstein RM, Schmid M, Fankhauser C. Genome Biol. 2025 Dec 10;26(1):422. doi: 10.1186/s13059-025-03901-2.PMID: 41372949
Background: Open chromatin regions host DNA regulatory motifs that are accessible to transcription factors and the transcriptional machinery. In Arabidopsis, responses to light are heavily regulated at the transcriptional level. Shade, for example, can limit photosynthesis and is rapidly perceived by phytochromes as a reduction of red to far-red light ratio (LRFR). Under shade, phytochromes become inactive, enabling PHYTOCHROME INTERACTING FACTORs (PIFs), particularly PIF7, to promote genome-wide reprogramming essential for LRFR responses. An initial strong and fast regulation of shade-responsive genes is followed by attenuation of this response under prolonged shade.
Results: To determine whether the transcriptional response to shade depends on chromatin accessibility, we use ATAC-seq to profile the chromatin of seedlings exposed to short (1 h) and long (25 h) simulated shade. We find that PIF7 binding sites are accessible for most early target genes before LRFR treatment. The transcription pattern of most acute shade-responsive genes correlates with a rapid increase in PIF levels and chromatin association at 1 h, and its decrease at 25 h of shade exposure. For a small subset of acutely responding genes, PIFs also modulate chromatin accessibility at their binding sites early and/or late in the response to shade.
Conclusions: Our results suggest that in seedlings a state of open chromatin conformation allows PIFs to easily access and recognize their binding motifs, rapidly initiating gene expression triggered by shade. This transcriptional response primarily depends on a transient increase in PIF stability and gene occupancy, accompanied by changes in chromatin accessibility in a minority of genes.
Keywords: ATAC-seq; Arabidopsis; Chromatin accessibility; PIF7; Shade; Transcription.
© 2025. The Author(s).
Calum Forteath 1 , Heather J Merchant 1 , Cyril Kocherry 1 , Colin E Murdoch 2 , Jennifer Kerr 1 , Jennifer R Gallagher 1 , Mark L Evans 3 , Bernard Thorens 4 , Ulrik Pedersen-Bjergaard 5 6 , Bastiaan E de Galan 7 8 9 , Rory J McCrimmon 10 , Alison D McNeilly 11 ; Hypo-RESOLVE Consortium
Aims/hypothesis: CVD remains the leading cause of mortality in individuals with type 1 diabetes over the age of 40 years. Although intensive insulin therapy lowers chronic hyperglycaemia and improves cardiovascular outcomes, it also increases the frequency of hypoglycaemic episodes, an emerging but poorly understood contributor to CVD risk. The mechanisms by which recurrent hypoglycaemia exacerbates cardiovascular pathology in type 1 diabetes are unknown.
Methods: Using a C57BL/J streptozocin-induced male mouse model of type 1 diabetes, combined with detailed physiological and molecular assessments, we investigated the impact of recurrent hypoglycaemia (<3.0 mmol/l) on cardiovascular structure and function using laser Doppler imaging with iontophoresis and ultrasound imaging.
Results: Type 1 diabetes induces significant microvascular endothelial dysfunction, which is worsened by recurrent hypoglycaemia. Chronic exposure to hypoglycaemia (60 episodes over 20 weeks) resulted in compensatory shifts in cardiac haemodynamics, which in type 1 diabetic mice but not non-diabetic mice resulted in early dilated cardiomyopathy. In both type 1 diabetic and non-diabetic mice, recurrent hypoglycaemia resulted in impaired systolic function during a subsequent hypoglycaemic challenge, indicating increased cardiac vulnerability despite any compensatory changes. Transcriptomic profiling of left ventricular tissue revealed that recurrent hypoglycaemia induces distinct gene expression changes involving ion homeostasis, repolarisation dynamics and microvascular signalling-molecular alterations characteristic of early diabetic cardiomyopathy.
Conclusions/interpretation: These findings provide the first in vivo evidence that recurrent hypoglycaemia synergises with hyperglycaemia to accelerate microvascular dysfunction and adverse cardiac remodelling in type 1 diabetes. This work identifies a novel mechanistic link between hypoglycaemia and diabetic heart disease, underscoring the need for therapeutic strategies that mitigate glycaemic variability without increasing the hypoglycaemic burden.