m6a methylation orchestrates IMP1 regulation of microtubules during human neuronal differentiation

Pierre Klein, Marija Petrić Howe, Jasmine Harley, Harry Crook, Sofia Esteban Serna, Theodoros I. Roumeliotis, Jyoti S. Choudhary, Anob M. Chakrabarti, Raphaëlle Luisier, Rickie Patani () and Andres Ramos ()
Additional contact information
Pierre Klein: Darwin Building
Marija Petrić Howe: The Francis Crick Institute
Jasmine Harley: The Francis Crick Institute
Harry Crook: The Francis Crick Institute
Sofia Esteban Serna: Darwin Building
Theodoros I. Roumeliotis: The Institute of Cancer Research
Jyoti S. Choudhary: The Institute of Cancer Research
Anob M. Chakrabarti: The Francis Crick Institute
Raphaëlle Luisier: Idiap Research Institute
Rickie Patani: The Francis Crick Institute
Andres Ramos: Darwin Building

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: Abstract Neuronal differentiation requires building a complex intracellular architecture, and therefore the coordinated regulation of defined sets of genes. RNA-binding proteins (RBPs) play a key role in this regulation. However, while their action on individual mRNAs has been explored in depth, the mechanisms used to coordinate gene expression programs shaping neuronal morphology are poorly understood. To address this, we studied how the paradigmatic RBP IMP1 (IGF2BP1), an essential developmental factor, selects and regulates its RNA targets during the human neuronal differentiation. We perform a combination of system-wide and molecular analyses, revealing that IMP1 developmentally transitions to and directly regulates the expression of mRNAs encoding essential regulators of the microtubule network, a key component of neuronal morphology. Furthermore, we show that m6A methylation drives the selection of specific IMP1 mRNA targets and their protein expression during the developmental transition from neural precursors to neurons, providing a molecular principle for the onset of target selectivity.

Date: 2024
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DOI: 10.1038/s41467-024-49139-7

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