The Heterochromatin protein 1 is a regulator in RNA splicing precision deficient in ulcerative colitis

Jorge Mata-Garrido, Yao Xiang, Yunhua Chang-Marchand, Caroline Reisacher, Elisabeth Ageron, Ida Chiara Guerrera, Iñigo Casafont, Aurelia Bruneau, Claire Cherbuy, Xavier Treton, Anne Dumay, Eric Ogier-Denis, Eric Batsché, Mickael Costallat, Gwladys Revêchon, Maria Eriksson, Christian Muchardt and Laurence Arbibe ()
Additional contact information
Jorge Mata-Garrido: Université Paris Cité, INSERM, CNRS, Institut Necker Enfants Malades
Yao Xiang: Université Paris Cité, INSERM, CNRS, Institut Necker Enfants Malades
Yunhua Chang-Marchand: Université Paris Cité, INSERM, CNRS, Institut Necker Enfants Malades
Caroline Reisacher: Université Paris Cité, INSERM, CNRS, Institut Necker Enfants Malades
Elisabeth Ageron: Université Paris Cité, INSERM, CNRS, Institut Necker Enfants Malades
Ida Chiara Guerrera: Université Paris Cité-Structure Fédérative de Recherche Necker, INSERM US24/CNRS UAR3633
Iñigo Casafont: Institute Valdecilla-IDIVAL
Aurelia Bruneau: Institut National de Recherche pour L’agriculture, L’alimentation et L’environnement (INRAE), AgroParisTech, Université Paris-Saclay, UMR1319
Claire Cherbuy: Institut National de Recherche pour L’agriculture, L’alimentation et L’environnement (INRAE), AgroParisTech, Université Paris-Saclay, UMR1319
Xavier Treton: UMR-S 1149, Université Paris Cité, Inserm, Centre de recherche sur l’inflammation, équipe Inflammation intestinale
Anne Dumay: UMR-S 1149, Université Paris Cité, Inserm, Centre de recherche sur l’inflammation, équipe Inflammation intestinale
Eric Ogier-Denis: UMR-S 1149, Université Paris Cité, Inserm, Centre de recherche sur l’inflammation, équipe Inflammation intestinale
Eric Batsché: Sorbonne Université, Institut de Biologie Paris-Seine (IBPS), CNRS Unit of Biological Adaptation and Ageing (B2A), Epigenetics and RNA metabolism in human diseases
Mickael Costallat: Sorbonne Université, Institut de Biologie Paris-Seine (IBPS), CNRS Unit of Biological Adaptation and Ageing (B2A), Epigenetics and RNA metabolism in human diseases
Gwladys Revêchon: Karolinska Institutet
Maria Eriksson: Karolinska Institutet
Christian Muchardt: Sorbonne Université, Institut de Biologie Paris-Seine (IBPS), CNRS Unit of Biological Adaptation and Ageing (B2A), Epigenetics and RNA metabolism in human diseases
Laurence Arbibe: Université Paris Cité, INSERM, CNRS, Institut Necker Enfants Malades

Nature Communications, 2022, vol. 13, issue 1, 1-16

Abstract: Abstract Defects in RNA splicing have been linked to human disorders, but remain poorly explored in inflammatory bowel disease (IBD). Here, we report that expression of the chromatin and alternative splicing regulator HP1γ is reduced in ulcerative colitis (UC). Accordingly, HP1γ gene inactivation in the mouse gut epithelium triggers IBD-like traits, including inflammation and dysbiosis. In parallel, we find that its loss of function broadly increases splicing noise, favoring the usage of cryptic splice sites at numerous genes with functions in gut biology. This results in the production of progerin, a toxic splice variant of prelamin A mRNA, responsible for the Hutchinson-Gilford Progeria Syndrome of premature aging. Splicing noise is also extensively detected in UC patients in association with inflammation, with progerin transcripts accumulating in the colon mucosa. We propose that monitoring HP1γ activity and RNA splicing precision can help in the management of IBD and, more generally, of accelerated aging.

Date: 2022
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DOI: 10.1038/s41467-022-34556-3

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