Biochim Biophys Acta Mol Cell Res, auth.: group Fajas

. 2024 Apr 3:119721.

 doi: 10.1016/j.bbamcr.2024.119721. Online ahead of print.

E2F transcription factor-1 modulates expression of glutamine metabolic genes in mouse embryonic fibroblasts and uterine sarcoma cells

Katharina Huber 1Albert Giralt 2René Dreos 2Helene Michenthaler 3Sarah Geller 2Valentin Barquissau 2Dorian V Ziegler 2Daniele Tavernari 4Hector Gallart-Ayala 5Katarina Krajina 6Katharina Jonas 6Giovanni Ciriello 4Julijana Ivanisevic 5Andreas Prokesch 7Martin Pichler 8Lluis Fajas 9

Affiliations expand

Abstract

Metabolic reprogramming is considered as a hallmark of cancer and is clinically exploited as a novel target for therapy. The E2F transcription factor-1 (E2F1) regulates various cellular processes, including proliferative and metabolic pathways, and acts, depending on the cellular and molecular context, as an oncogene or tumor suppressor. The latter is evident by the observation that E2f1-knockout mice develop spontaneous tumors, including uterine sarcomas. This dual role warrants a detailed investigation of how E2F1 loss impacts metabolic pathways related to cancer progression. Our data indicate that E2F1 binds to the promoter of several glutamine metabolism-related genes. Interestingly, the expression of genes in the glutamine metabolic pathway were increased in mouse embryonic fibroblasts (MEFs) lacking E2F1. In addition, we confirm that E2f1-/- MEFs are more efficient in metabolizing glutamine and producing glutamine-derived precursors for proliferation. Mechanistically, we observe a co-occupancy of E2F1 and MYC on glutamine metabolic promoters, increased MYC binding after E2F1 depletion and that silencing of MYC decreased the expression of glutamine-related genes in E2f1-/- MEFs. Analyses of transcriptomic profiles in 29 different human cancers identified uterine sarcoma that showed a negative correlation between E2F1 and glutamine metabolic genes. CRISPR/Cas9 knockout of E2F1 in the uterine sarcoma cell line SK-UT-1 confirmed elevated glutamine metabolic gene expression, increased proliferation and increased MYC binding to glutamine-related promoters upon E2F1 loss. Together, our data suggest a crucial role of E2F1 in energy metabolism and metabolic adaptation in uterine sarcoma cells.

Nat Cell Biol, auth.: group Vastenhouw

. 2024 Apr 8.

 doi: 10.1038/s41556-024-01389-9. Online ahead of print.

Transcription bodies regulate gene expression by sequestering CDK9

Martino Ugolini 1 2Maciej A Kerlin 1Ksenia Kuznetsova 2Haruka Oda 3 4Hiroshi Kimura 3Nadine L Vastenhouw 5 6

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Abstract

The localization of transcriptional activity in specialized transcription bodies is a hallmark of gene expression in eukaryotic cells. It remains unclear, however, if and how transcription bodies affect gene expression. Here we disrupted the formation of two prominent endogenous transcription bodies that mark the onset of zygotic transcription in zebrafish embryos and analysed the effect on gene expression using enriched SLAM-seq and live-cell imaging. We find that the disruption of transcription bodies results in the misregulation of hundreds of genes. Here we focus on genes that are upregulated. These genes have accessible chromatin and are poised to be transcribed in the presence of the two transcription bodies, but they do not go into elongation. Live-cell imaging shows that disruption of the two large transcription bodies enables these poised genes to be transcribed in ectopic transcription bodies, suggesting that the large transcription bodies sequester a pause release factor. Supporting this hypothesis, we find that CDK9-the kinase that releases paused polymerase II-is highly enriched in the two large transcription bodies. Overexpression of CDK9 in wild-type embryos results in the formation of ectopic transcription bodies and thus phenocopies the removal of the two large transcription bodies. Taken together, our results show that transcription bodies regulate transcription by sequestering machinery, thereby preventing genes elsewhere in the nucleus from being transcribed.

Cell, co-auth.: L.Michalik

. 2024 Mar 14;187(6):1335-1342.

 doi: 10.1016/j.cell.2024.01.050.

Closing the scissor-shaped curve: Strategies to promote gender equality in academia

Johanna A Joyce 1Slavica Masina 2Liliane Michalik 3Caroline Pot 4Christine Sempoux 5Francesca Amati 6

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Abstract

Gender inequality in STEM fields remains pervasive and undermines the ability for talented individuals to excel. Despite advances, women still encounter obstacles in pursuing academic careers and reaching leadership positions. This commentary discusses the “scissor-shaped curve” and examines effective strategies to fix it, including data-driven initiatives that we have implemented at our university.

Clin Epigenetics, co-auth. group Reymond

Observational Study

. 2024 Feb 28;16(1):36.

 doi: 10.1186/s13148-024-01648-4.

DNA methylation may partly explain psychotropic drug-induced metabolic side effects: results from a prospective 1-month observational study

Céline Dubath 1Eleonora Porcu 2 3 4Aurélie Delacrétaz 5Claire Grosu 5Nermine Laaboub 5Marianna Piras 5Armin von Gunten 6Philippe Conus 7Kerstin Jessica Plessen 8Zoltán Kutalik 2 4 9Chin Bin Eap 10 11 12 13

Affiliations expand

Abstract

Background: Metabolic side effects of psychotropic medications are a major drawback to patients’ successful treatment. Using an epigenome-wide approach, we aimed to investigate DNA methylation changes occurring secondary to psychotropic treatment and evaluate associations between 1-month metabolic changes and both baseline and 1-month changes in DNA methylation levels. Seventy-nine patients starting a weight gain inducing psychotropic treatment were selected from the PsyMetab study cohort. Epigenome-wide DNA methylation was measured at baseline and after 1 month of treatment, using the Illumina Methylation EPIC BeadChip.

Results: A global methylation increase was noted after the first month of treatment, which was more pronounced (p < 2.2 × 10-16) in patients whose weight remained stable (< 2.5% weight increase). Epigenome-wide significant methylation changes (p < 9 × 10-8) were observed at 52 loci in the whole cohort. When restricting the analysis to patients who underwent important early weight gain (≥ 5% weight increase), one locus (cg12209987) showed a significant increase in methylation levels (p = 3.8 × 10-8), which was also associated with increased weight gain in the whole cohort (p = 0.004). Epigenome-wide association analyses failed to identify a significant link between metabolic changes and methylation data. Nevertheless, among the strongest associations, a potential causal effect of the baseline methylation level of cg11622362 on glycemia was revealed by a two-sample Mendelian randomization analysis (n = 3841 for instrument-exposure association; n = 314,916 for instrument-outcome association).

Conclusion: These findings provide new insights into the mechanisms of psychotropic drug-induced weight gain, revealing important epigenetic alterations upon treatment, some of which may play a mediatory role.

Nat Genet, co-auth.: MC Gambetta

Enhancer-promoter interactions become more instructive in the transition from cell-fate specification to tissue differentiation

Tim Pollex 1 2Adam Rabinowitz 1Maria Cristina Gambetta 1 3Raquel Marco-Ferreres 1Rebecca R Viales 1Aleksander Jankowski 1 4Christoph Schaub 1Eileen E M Furlong 5

. 2024 Mar 11.

Abstract

To regulate expression, enhancers must come in proximity to their target gene. However, the relationship between the timing of enhancer-promoter (E-P) proximity and activity remains unclear, with examples of uncoupled, anticorrelated and correlated interactions. To assess this, we selected 600 characterized enhancers or promoters with tissue-specific activity in Drosophila embryos and performed Capture-C in FACS-purified myogenic or neurogenic cells during specification and tissue differentiation. This enabled direct comparison between E-P proximity and activity transitioning from OFF-to-ON and ON-to-OFF states across developmental conditions. This showed remarkably similar E-P topologies between specified muscle and neuronal cells, which are uncoupled from activity. During tissue differentiation, many new distal interactions emerge where changes in E-P proximity reflect changes in activity. The mode of E-P regulation therefore appears to change as embryogenesis proceeds, from largely permissive topologies during cell-fate specification to more instructive regulation during terminal tissue differentiation, when E-P proximity is coupled to activation.

New Phytol, auth.: M.Legris

Light and temperature regulation of leaf morphogenesis in Arabidopsis

. 2023 Dec;240(6):2191-2196.

 doi: 10.1111/nph.19258. Epub 2023 Sep 15.

  • PMID: 37715490
  • DOI: 10.1111/nph.19258
  • Abstract
  • Leaves are the main photosynthetic organs in plants, and their anatomy is optimized for light interception and gas exchange. Although each species has a characteristic leaf anatomy, which depends on the genotype, leaves also show a large degree of developmental plasticity. Light and temperature regulate leaf development from primordia differentiation to late stages of blade expansion. While the molecular mechanisms of light and temperature signaling have been mostly studied in seedlings, in the latest years, research has focused on leaf development. Here, I will describe the latest work carried out in the environmental regulation of Arabidopsis leaf development, comparing signaling mechanisms between leaves and seedlings, highlighting the new discoveries, and pointing out the most exciting open questions.