Anna Fleming1,8, Elena V. Knatko1, Xiang Li1, Ansgar Zoch2,3,9, Zoe Heckhausen4,5, Stephanie Stransky6, Alejandro J. Brenes7, Simone Sidoli6, Petra Hajkova4,5, Dónal O'Carroll2,3 and Kasper D. Rasmussen1 1Division of Molecular, Cellular, and Developmental Biology, University of Dundee, Dundee DD1 5EH, United Kingdom; 2Centre for Regenerative Medicine, Institute for Regeneration and Repair, Institute for Stem Cell Research, University of Edinburgh, Edinburgh EH16 4UU, United Kingdom; 3Wellcome Centre for Cell Biology, University of Edinburgh, Edinburgh EH9 3BF, United Kingdom; 4MRC Laboratory of Medical Sciences, London W12 0NN, United Kingdom; 5Institute of Clinical Sciences, Faculty of Medicine, Imperial College London, London SW7 2AZ, United Kingdom; 6Department of Biochemistry, Albert Einstein College of Medicine, Bronx, New York 10461, USA; 7Division of Cell Signalling and Immunology, University of Dundee, Dundee DD1 5EH, United Kingdom Corresponding author: kdrasmussendundee.ac.uk

↵Present addresses: 8Department of Medical and Molecular Genetics, Faculty of Life Sciences and Medicine, King's College London, London SE1 9RT, UK; 9MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, UK.

Abstract

The link between DNA methylation and neurodevelopmental disorders is well established. However, how DNA methylation is fine-tuned—ensuring precise gene expression and developmental fidelity—remains poorly understood. PROSER1, a known TET2 interactor, was recently linked to a severe neurodevelopmental disorder. Here, we demonstrate that PROSER1 interacts with all TET enzymes and stabilizes chromatin-bound TET–OGT–PROSER1–DBHS (TOPD) complexes, which regulate DNA demethylation and developmental gene expression. Surprisingly, we found that PROSER1 also sequesters TET enzymes, preventing widespread demethylation and transposable element derepression. Our findings identify PROSER1 as a key factor that both positively and negatively regulates DNA demethylation essential for mammalian neurodevelopment.

Received July 31, 2024. Accepted October 15, 2024.