SINEUP RNA rescues molecular phenotypes associated with CHD8 suppression in autism spectrum disorder model systems
Loss-of-function mutations in the chromodomain helicase DNA-binding 8 (CHD8) gene are strongly associated with autism spectrum disorders (ASDs). Indeed, the reduction of CHD8 causes transcriptional, epigenetic, and cellular phenotypic changes correlated to disease, which can be monitored in assessing new therapeutic approaches. SINEUPs are a functional class of natural and synthetic antisense long non-coding RNAs able to stimulate the translation of sense target mRNA, with no effect on transcription. Here, we employed synthetic SINEUP-CHD8 targeting the first and third AUG of the CHD8 coding sequence to efficiently stimulate endogenous CHD8 protein production. SINEUP-CHD8 were effective in cells with reduced levels of the target protein and in patient-derived fibroblasts with CHD8 mutations. Functionally, SINEUP-CHD8 were able to revert molecular phenotypes associated with CHD8 suppression, i.e., genome-wide transcriptional dysregulation, and the reduction of H3K36me3 levels. Strikingly, in chd8-morpholino-treated and ENU mutant zebrafish embryos, SINEUP-chd8 injection confirmed the ability of SINEUP RNA to rescue the chd8-suppression-induced macrocephaly phenotype and neuronal hyperproliferation. Thus, SINEUP-CHD8 molecule(s) represent a proof-of-concept toward the development of an RNA-based therapy for neurodevelopmental syndromes with implications for, and beyond ASD, and relevant to genetic disorders caused by protein haploinsufficiency.
Authors
- S. Zucchelli (ORCID: https://orcid.org/0000-0003-4556-2990)
- Jasmin Morandell (ORCID: https://orcid.org/0000-0003-1190-8236)
- Christelle Golzio (ORCID: https://orcid.org/0000-0002-4420-3921)
- Stefano Gustincich (ORCID: https://orcid.org/0000-0002-2749-2514)
- Michele Arnoldi
- Giulia Zarantonello (ORCID: https://orcid.org/0000-0002-6742-9237)
- Carlotta Bon (ORCID: https://orcid.org/0000-0002-7443-4659)
- Stefano Espinoza (ORCID: https://orcid.org/0000-0002-3048-4822)
- Giuseppe Ronzitti (ORCID: https://orcid.org/0000-0002-9184-0210)
- Francesca Di Leva (ORCID: https://orcid.org/0000-0002-6167-0679)
- Yuri Bozzi (ORCID: https://orcid.org/0000-0002-1496-9889)
- Marta Biagioli (ORCID: https://orcid.org/0000-0001-8295-8025)
- Andrea Messina (ORCID: https://orcid.org/0000-0001-7363-4301)
- Miguel Pellegrini
- Simona Casarosa (ORCID: https://orcid.org/0000-0002-7744-8183)
- Stefania Santarelli
- Erik Dassi (ORCID: https://orcid.org/0000-0003-4487-0449)
- Maria Elena Castellini (ORCID: https://orcid.org/0000-0002-8213-3565)
- Mathieu Massonot (ORCID: https://orcid.org/0000-0003-4718-9798)
- Marianne Victoria Lemée (ORCID: https://orcid.org/0000-0002-4897-0722)
- Raphael Bernier
Institutions
- Università degli Studi del Piemonte Orientale “Amedeo Avogadro” (IT)
- Centre National de la Recherche Scientifique (FR)
- Inserm (FR)
- University of Trento (IT)
- University of Washington (US)
- Université Paris-Saclay (FR)
- Italian Institute of Technology (IT)
- Institut de génétique et de biologie moléculaire et cellulaire (FR)
- Behavioral Tech Research, Inc. (US)
- Genethon (France) (FR)
- Université de Strasbourg (FR)
Publication Details
- Journal
- Molecular Therapy
- Published
- 2024-12-30
- DOI
- https://doi.org/10.1016/j.ymthe.2024.12.043
- Citations
- 8
- Primary Topic
- RNA modifications and cancer
- Type
- article
- Field-Weighted Citation Impact
- 1.87
Funders
- Brain and Behavior Research Foundation
- Simons Foundation Autism Research Initiative
- Agence Nationale de la Recherche