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bioRxiv · 10.1101/2024.07.31.606086

PROSER1 Modulates DNA Demethylation through Dual Mechanisms to Prevent Syndromic Developmental Malformations

Fleming, A.·Knatko, E. V.·Li, X.·Zoch, A.·Heckhausen, Z.·Stransky, S.·Brenes, A. J.·Sidoli, S.·Hajkova, P.·O'Carroll, D.·Rasmussen, K. D.
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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 find that PROSER1 also sequesters TET enzymes, preventing widespread demethylation and transposable element de-repression. Our findings identify PROSER1 as a key factor which both positively and negatively regulates DNA demethylation essential for mammalian neurodevelopment.

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Fleming, A., Knatko, E. V., Li, X., Zoch, A., Heckhausen, Z., Stransky, S., Brenes, A. J., Sidoli, S., Hajkova, P., O'Carroll, D., Rasmussen, K. D.. 2024-08-02. PROSER1 Modulates DNA Demethylation through Dual Mechanisms to Prevent Syndromic Developmental Malformations. https://doi.org/10.1101/2024.07.31.606086

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