Nuclear class 3 PI3K co-activates fasting-specific chromatin remodelling
Transcriptional remodelling during fasting ensures metabolic adaptation and provides health benefits across species. Although several regulators of fasting-induced transcription and chromatin are known, how nutrient levels directly influence RNA polymerase II (RNAPII) and epigenetic writers remains unclear. Here we show that lipid kinase class 3 phosphatidylinositol 3-kinase (PI3K-3), a master regulator of autophagy, also functions on chromatin as a co-activator of epigenetic writers to promote RNAPII transcription. PI3K-3 overlaps with transcriptionally engaged RNAPII phosphorylated at Ser5 and with Setd1a/COMPASS, the complex that deposits the activating H3K4me3 mark. Nuclear PI3K-3 interacts with RNAPII and Setd1a/COMPASS and promotes their chromatin binding. PI3K-3 loss reduces RNAPII-S5p and H3K4me3 at selected genes, whereas PI3K-3 overexpression co-activates p300/CBP and chromatin-targeted PI3K-3 increases H3K4me3. During starvation, PI3K-3 induces autophagy genes and drives fasted liver towards ketogenesis and lipid degradation. These findings link nutrient stress to chromatin-mediated transcriptional activation. Henneman et al. report an unexpected role for class 3 PI3K (PI3K-3) acting as a transcriptional co-activator during fasting. They show that nuclear PI3K-3 co-activates the methyltransferase Set1/COMPASS complex to promote H3K4me3 deposition.
Authors
- Dominik Lutter (ORCID: https://orcid.org/0000-0002-8800-0683)
- Samuel Le Cam (ORCID: https://orcid.org/0000-0002-7172-6226)
- Nicolas Cagnard (ORCID: https://orcid.org/0000-0002-9051-1896)
- Nathaniel F. Henneman
- Raphaël Margueron (ORCID: https://orcid.org/0000-0002-9093-7977)
- Takeaki Ozawa (ORCID: https://orcid.org/0000-0002-3198-4853)
- Ivan Nemazanyy (ORCID: https://orcid.org/0000-0001-8080-839X)
- Calvin Rodrigues (ORCID: https://orcid.org/0000-0003-1857-9500)
- Genki Kawamura (ORCID: https://orcid.org/0000-0002-5098-0911)
- Nicolas Kuperwasser (ORCID: https://orcid.org/0000-0002-7841-3214)
- Ganna Panasyuk (ORCID: https://orcid.org/0000-0002-5591-848X)
- Karim Hnia (ORCID: https://orcid.org/0000-0001-5298-3000)
- Ying Luo (ORCID: https://orcid.org/0000-0003-1878-7641)
- Arianna Segaloni
- Jiaqi Su (ORCID: https://orcid.org/0000-0001-6038-0808)
- Catia Oliveira Dias
Institutions
- Centre National de la Recherche Scientifique (FR)
- Université Toulouse III - Paul Sabatier (FR)
- Inserm (FR)
- Tokyo University of Science (JP)
- Université Paris Cité (FR)
- Université Paris Sciences et Lettres (FR)
- Helmholtz Zentrum München (DE)
- Sorbonne Université (FR)
- Institut Necker Enfants Malades (FR)
- Sorbonne Paris Cité (FR)
- Institut des Maladies Métaboliques et Cardiovasculaires (FR)
- Deutsches Diabetes-Zentrum e.V. (DE)
- German Center for Diabetes Research (DE)
- Heinrich Heine University Düsseldorf (DE)
Publication Details
- Journal
- Nature Cell Biology
- Published
- 2026-07-28
- DOI
- https://doi.org/10.1038/s41556-026-02030-7
- Primary Topic
- Autophagy in Disease and Therapy
- Type
- article
- Field-Weighted Citation Impact
- 0.00