Deciphering the conserved role of neuronal JMJD3 in adapting metabolism and behavior across generations

• Applicant: Merly Vogt, Ph.D.
• Subject Area: Molecular Biology and Physiology of Neurons and Glial Cells ; Cell Biology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 572806210

Exposure to adverse nutritional environments during critical developmental windows can profoundly impact metabolic and neurological health across multiple generations. This phenomenon, termed "metabolic programming" has been documented in diverse species, including nematodes, mice, and humans, indicating highly conserved underlying mechanisms. While emerging evidence emphasizes the central nervous system (CNS) as both a key mediator and a primary target of metabolic programming, the precise signaling pathways and underlying molecular mechanisms driving health impairments across generations remain poorly understood. The histone demethylase JMJD3/JMJD-3.1 (Jumanji domain-containing protein 3), specifically demethylating histone 3 lysine 27 trimethylation (H3K27me3), has been implicated in metabolic and stress responses. Previously, nutritional regulation of JMJD3 has primarily been studied in mammalian liver during fasting conditions. However, my preliminary studies have identified a novel, neuron-specific dietary regulation of JMJD-3.1 in C. elegans, and its mammalian homolog JMJD3 in mice, highlighting its dynamic expression in response to dietary challenges. Notably, nematodes exposed to a high-fat diet (HFD) exhibit altered jmjd-3.1 expression alongside increased fat storage, decreased lifespan, and aberrant exploratory behavior. Strikingly, these phenotypes are rescued by neuron-specific JMJD-3.1 depletion in the exposed (P0) generation, suggesting a pivotal role for neuronal JMJD-3.1 in mediating adaptive responses to nutritional stress. This project aims to elucidate the role of neuronal JMJD-3.1/JMJD3 using integrated experimental approaches across C. elegans and mouse models. Specifically, we will (1) determine how dietary-induced neuronal JMJD-3.1 activity contributes to metabolic dysfunction and lifespan reduction in the exposed (P0) generation of C. elegans, identifying transcriptional and epigenetic changes in neurons and establishing causal relationships. Moreover, we will (2) uncover the molecular and cell type-specific mechanisms by which JMJD-3.1 mediates intergenerational transmission of diet-induced metabolic and behavioral phenotypes in the F1 generation, distinguishing neuronal (indirect) versus germline (direct) contributions. Finally, we will (3) explore the role of hypothalamic JMJD3 in mammalian models, employing AgRP-Cre-specific knockout mice to assess sex- and diet-specific metabolic and behavioral outcomes, along with transcriptomic and epigenetic profiling. Leveraging advanced genetic tools in C. elegans and precise mouse genetic models, this project will provide fundamental insights into conserved neuronal and epigenetic mechanisms underlying metabolic programming both within, and across generations, informing future strategies to address metabolic and neurological disorders linked to nutritional stress.

• DFG Programme: Research Grants