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

Affiliations expand

• PMID: 38419113
• PMCID: PMC10903022
• DOI: 10.1186/s13148-024-01648-4

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.

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

Tim Pollex ^1 2, Adam Rabinowitz ¹, Maria Cristina Gambetta ^1 3, Raquel Marco-Ferreres ¹, Rebecca R Viales ¹, Aleksander Jankowski ^1 4, Christoph Schaub ¹, Eileen 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.

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.

GDF15 activates AMPK and inhibits gluconeogenesis and fibrosis in the liver by attenuating the TGF-β1/SMAD3 pathway

Javier Jurado-Aguilar ¹, Emma Barroso ¹, Maribel Bernard ¹, Meijian Zhang ¹, Mona Peyman ¹, Patricia Rada ², Ángela M Valverde ², Walter Wahli ³, Xavier Palomer ¹, Manuel Vázquez-Carrera ⁴

. 2024 Jan 3:152:155772.

 doi: 10.1016/j.metabol.2023.155772. Online ahead of print.

• PMID: 38176644
• DOI: 10.1016/j.metabol.2023.155772

Abstract

Introduction: The levels of the cellular energy sensor AMP-activated protein kinase (AMPK) have been reported to be decreased via unknown mechanisms in the liver of mice deficient in growth differentiation factor 15 (GDF15). This stress response cytokine regulates energy metabolism mainly by reducing food intake through its hindbrain receptor GFRAL.

Rare copy-number variants as modulators of common disease susceptibility

Chiara Auwerx ^1 2 3 4, Maarja Jõeloo ^5 6, Marie C Sadler ^7 8 9, Nicolò Tesio ¹⁰, Sven Ojavee ^7 8, Charlie J Clark ¹⁰, Reedik Mägi ⁶; Estonian Biobank Research Team; Alexandre Reymond ^# 11, Zoltán Kutalik ^{# 12 13 14}

Genome Med. 2024 Jan 8;16(1):5. doi: 10.1186/s13073-023-01265-5.

Abstract

Background: Copy-number variations (CNVs) have been associated with rare and debilitating genomic disorders (GDs) but their impact on health later in life in the general population remains poorly described.