Talks by Pierre KLEIN and Carine TISNE

Pierre KLEIN
Francis Crick Institute and UCL, London
Current: Inserm UMRS 974, Sorbonne Université Centre de Recherche en Myologie, Institut de myologie

Title:
m6a methylation orchestrates IMP1 regulation of microtubules during human neuronal differentiation

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.

Carine TISNE
IBPC, Laboratory of Microbial Gene Expression, UMR 8261 CNRS/University of Paris Cité, Paris, France,carine.tisne@cnrs.fr

Title:
Advances in the structural and functional understanding of m1A modifications

Abstract:
RNA modification is a co- or post-transcriptional process by which specific nucleotides are chemically altered by enzymes after their initial incorporation into the RNA chain, expanding the chemical and functional diversity of RNAs. Our understanding of RNA modifications has changed dramatically in recent years. In the last decade, RNA methyltransferases (MTases) have been highlighted in numerous clinical studies and disease models, modifications were found to be dynamically regulated by de-modification enzymes, and significant technological advances have been made in the field of RNA sequencing, mass spectrometry and structural biology. The mono-methylation of adenine at position N1 (m 1 A) are frequently occurring methylations in RNAs. Among RNAs, transfer RNAs (tRNAs) exhibit the greatest diversity and density of post-transcriptional modifications, which allows for potential cross-talks and regulation during their incorporation. The N1-methyladenosine (m 1 A) modification is found in tRNAs at position 9, 14, 16, 22, 57 and 58, depending on the tRNA and organism. My team has used and developed a large panel of tools to decipher the different mechanisms used by m 1 A tRNA MTases to recognize and methylate tRNA. Recent results will be presented.

References: Meynier V, Hardwick SW, Catala M, Roske JJ, Oerum S, Chirgadze DY, Barraud P, Yue WW, Luisi BF, Tisné C. (2024) Structural basis for human mitochondrial tRNA maturation. Nat Commun. 15, p. 4683. doi: 10.1038/s41467-024-49132-0. Smoczynski J, Yared MJ, Meynier V, Barraud P, Tisné C. (2024) Advances in the structural and functional understanding of m1A RNA modification. Acc Chem Res. 57, p. 29-38. doi: 10.1021/acs.accounts.3c00568. Yared MJ, Yoluç Y, Catala M, Tisné C, Kaiser S, Barraud P. (2023) Different modification pathways for m1A58 incorporation in yeast elongator and initiator tRNAs. Nucleic Acids Res. 51, p. 10653-10667. doi: 10.1093/nar/gkad722. Barraud P, Gato A, Heiss M, Catala M, Kellner S, Tisné C. (2019) Time-resolved NMR monitoring of tRNA maturation. Nat Commun. 10, p. 3373. doi: 10.1038/s41467-019-11356-w. Dégut C, Roovers M, Barraud P, Brachet F, Feller A, Larue V, Al Refaii A, Caillet J, Droogmans L, Tisné C. (2019) Structural characterization of B. subtilis m1A22 tRNA methyltransferase TrmK: insights into tRNA recognition. Nucleic Acids Res. 47, p. 4736-4750. doi: 10.1093/nar/gkz230.