BioRxiv auth.: group Michalik

Estrogen Receptors/E2F1/CDKN3 Axis Protects from UV-induced Skin Cancers in Females

Céline Lukowicz, Carine Winkler, Catherine Roger, Joanna C Fowler, Yi-Chien Tsai, Joachim Meuli, Stéphanie Claudinot, Yun-Tsan Chang, Christoph Iselin,  View ORCID ProfilePhilip H Jones, Emmanuella Guenova, Paris Jafari, Liliane Michalik

doi: https://doi.org/10.1101/2025.02.12.637819

This article is a preprint and has not been certified by peer review [what does this mean?].

Abstract

Men have a significantly higher risk of developing cutaneous squamous cell carcinoma (SCC) compared to women, but models and comprehensive analysis of signaling pathways highlighting this sexual dimorphism are missing. In this study, we display a UV-induced SCC model in hairless mice recapitulating this sex difference, with enhanced SCC development in males. While UV-induced DNA damage is similar between sexes, we uncovered sex-specific responses in epidermal cell proliferation and differentiation. Using global transcriptional profile analyses, we identified E2F transcription factors as key sex-specific markers involved in the proliferative response to UV. Notably, E2F1/2, along with their target gene CDKN3, were selectively downregulated in female mice and human epidermis following UV exposure. Mechanistically, UV-induced and sex-specific modulation of E2F1 and CDKN3 expression is mediated by Estrogen Receptors. Lastly, low levels of CDKN3 in head and neck SCC are observed exclusively in female patients correlating with better prognosis. These findings shed new light on fundamental mechanisms protecting women from cancer after carcinogen exposure and could lead to better sex-targeted preventive and therapeutic strategies in SCC and other malignancies.

bioRxiv. auth.: co-auth.: group Fankhauser

[Preprint]. 2025 Mar 25:2025.03.23.644808.doi: 10.1101/2025.03.23.644808.

Canalization of flower production across thermal environments requires Florigen and CLAVATA signaling

Elizabeth S Smith 1Amala John 1Andrew C Willoughby 1Daniel S Jones 1Vinicius C Galvão 2Christian Fankhauser 2Zachary L Nimchuk 1 3

Affiliations Expand

Abstract

The ability to maintain invariant developmental phenotypes across disparate environments is termed canalization, but few examples of canalization mechanisms are described. In plants, robust flower production across environmental gradients contributes to reproductive success and agricultural yields. Flowers are produced by the shoot apical meristem (SAM) in an auxin-dependent manner following the switch from vegetative growth to the reproductive phase. While the timing of this phase change, called the floral transition, is sensitized to numerous environmental and endogenous signals, flower formation itself is remarkably invariant across environmental conditions. Previously we found that CLAVATA peptide signaling promotes auxin-dependent flower primordia formation in cool environments, but that high temperatures can restore primordia formation through unknown mechanisms. Here, we show that heat promotes floral primordia patterning and formation in SAMs not by increased auxin production, but through the production of the mobile flowering signal, florigen, in leaves. Florigen, which includes FLOWERING LOCUS T (FT) and its paralog TWIN SISTER OF FT (TSF) in Arabidopsis thaliana, is necessary and sufficient to buffer flower production against the loss of CLAVATA signaling and promotes heat-mediated primordia formation through specific SAM expressed transcriptional regulators. We find that sustained florigen production is necessary for continuous flower primordia production at warmer temperatures, contrasting florigen’s switch-like control of floral transition. Lastly, we show that CLAVATA signaling and florigen synergize to canalize flower production across broad temperature ranges. This work sheds light on the mechanisms governing the canalization of plant development and provides potential targets for engineering crop plants with improved thermal tolerances.

Genome Med. auth.: group Reymond

. 2025 Apr 14;17(1):38. doi: 10.1186/s13073-025-01463-3.

Bi-allelic variants in BRF2 are associated with perinatal death and craniofacial anomalies

Francesca Mattioli # 1Rún Friðriksdóttir # 2Anne Hebert # 1Sissy Bassani # 1Nazia Ibrahim 1 3Shagufta Naz 3Jacqueline Chrast 1Clara Pailler-Pradeau 1Ásmundur Oddsson 2Patrick Sulem 2Gisli H Halldorsson 2 4Páll Melsted 2 4Daníel F Guðbjartsson 2 4Flavia Palombo 5Tommaso Pippucci 6Nayereh Nouri 7Marco Seri 6Emily G Farrow 8 9Carol J Saunders 8 9Nicolas Guex 10Muhammad Ansar 11Kari Stefansson 2 12Alexandre Reymond 13 14

Affiliations Expand

Abstract

Background: Variants in genes encoding multiple subunits of the RNA Polymerase III complex which synthesizes rRNAs, tRNAs, and other small RNAs were previously associated with neurological disorders, such as syndromic hypomyelination leukodystrophies, pontocerebellar hypoplasia, and cerebellofaciodental syndrome. One new such candidate is BRF2, which encodes a TFIIB-like factor that recruits the RNA polymerase III complex to type 3 promoters to initiate transcription of U6, RnaseP, and 7SK RNAs.

Methods: We combined sequencing with functional analyses to investigate the effects of BRF2 variants.

Results: We observe that a previously reported significant underrepresentation of double transmission of a splice variant results in recessive lethality in three large Icelandic families with multiple perinatal losses. Using data aggregation, we identified an additional seven individuals worldwide from three unrelated families carrying biallelic variants in BRF2. Affected individuals present a variable phenotype ranging from severe craniofacial anomalies with early death to intellectual disability with motor and speech development. In silico 3D modelling and functional analyses showed functional impairment of the identified variants, e.g., differences in target loci occupancy. Zebrafish knocked down for the orthologous brf2 presented with abnormal escape response, reduced swimming velocity and head size, and craniofacial malformations. These defects were complemented by the human wild-type but not mutated BRF2 mRNA further demonstrating their deleteriousness.

Conclusions: Overall, our results support the association of biallelic BRF2 variants with a novel neurodevelopmental disease and provide an additional link between RNA polymerase III, its targets and craniofacial anomalies.

Genes Dev. auth.: group Gambetta

. 2025 Apr 16. doi: 10.1101/gad.352646.125. Online ahead of print.

A boundary-defining protein facilitates megabase-scale regulatory chromosomal loop formation in Drosophila neurons

Marion Mouginot 1Sahar Hani 1Pascal Cousin 1Julien Dorier 2 3Arianna Ravera 4Maria Cristina Gambetta 5

Affiliations Expand

Abstract

Regulatory elements, such as enhancers and silencers, control transcription by establishing physical proximity to target gene promoters. Neurons in flies and mammals exhibit long-range three-dimensional genome contacts, proposed to connect genes with distal regulatory elements. However, the relevance of these contacts for neuronal gene transcription and the mechanisms underlying their specificity necessitate further investigation. Here, we precisely disrupt several long-range contacts in fly neurons, demonstrating their importance for megabase-range gene regulation and uncovering a hierarchical process in their formation. We further reveal an essential role for the chromosomal boundary-forming protein Cp190 in anchoring many long-range contacts, highlighting a mechanistic interplay between boundary and loop formation. Finally, we develop an unbiased proteomics-based method to systematically identify factors required for specific long-range contacts. Our findings underscore the essential role of architectural proteins such as Cp190 in cell type-specific genome organization in enabling specialized neuronal transcriptional programs.

Comparative Study: PLoS Biol: auth.: group Benton

. 2025 Apr 29;23(4):e3003120.doi: 10.1371/journal.pbio.3003120. eCollection 2025 Apr.

Comparative single-cell transcriptomic atlases of drosophilid brains suggest glial evolution during ecological adaptation

Daehan Lee 1 2Michael P Shahandeh 1 3Liliane Abuin 1Richard Benton 1

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Abstract

To explore how brains change upon species evolution, we generated single-cell transcriptomic atlases of the central brains of three closely related but ecologically distinct drosophilids: the generalists Drosophila melanogaster and Drosophila simulans, and the noni fruit specialist Drosophila sechellia. The global cellular composition of these species’ brains is well-conserved, but we predicted a few cell types with different frequencies, notably perineurial glia of the blood-brain barrier, which we validate in vivo. Gene expression analysis revealed that distinct cell types evolve at different rates and patterns, with glial populations exhibiting the greatest divergence between species. Compared to the D. melanogaster brain, cellular composition and gene expression patterns are more divergent in D. sechellia than in D. simulans-despite their similar phylogenetic distance from D. melanogaster-indicating that the specialization of D. sechellia is reflected in the structure and function of its brain. Expression changes in D. sechellia include several metabolic signaling genes, suggestive of adaptations to its novel source of nutrition. Additional single-cell transcriptomic analysis on D. sechellia revealed genes and cell types responsive to dietary supplement with noni, pointing to glia as sites for both physiological and genetic adaptation to this fruit. Our atlases represent the first comparative datasets for “whole” central brains and provide a comprehensive foundation for studying the evolvability of nervous systems in a well-defined phylogenetic and ecological framework.

Cell Rep, auth.: group Benton and Auer

  •  2025 Apr 25;44(5):115615.doi: 10.1016/j.celrep.2025.115615. Online ahead of print.

Olfactory projection neuron rewiring in the brain of an ecological specialist

Benedikt R Dürr 1Enrico Bertolini 2Suguru Takagi 3Justine Pascual 2Liliane Abuin 3Giovanna Lucarelli 3Richard Benton 3Thomas O Auer 4

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Free article

Abstract

Animal behaviors can differ greatly between closely related species. These behavioral changes are frequently linked to sensory system modifications, but central brain cell-type alterations might also be involved. Here, we develop advanced genetic tools to compare homologous central neurons in Drosophila sechellia, an ecological specialist, with the generalist Drosophila melanogaster. Through systematic morphological analysis of olfactory projection neurons (PNs), we reveal that the global anatomy of these second-order neurons is conserved. However, high-resolution, quantitative comparisons identify a striking case of convergent rewiring of PNs in two olfactory pathways critical for D. sechellia’s host location. Calcium imaging and labeling of pre-synaptic sites in these evolved D. sechellia PNs indicate that species-specific connections with third-order partners are formed. This work demonstrates that peripheral sensory evolution is accompanied by selective wiring changes in the central brain to facilitate ecological specialization and paves the way to compare other cell types throughout the nervous system.