Natural SINEUP RNAs in Autism Spectrum Disorders: RAB11B-AS1 Dysregulation in a Neuronal CHD8 Suppression Model Leads to RAB11B Protein Increase

CHD8 represents one of the highest confidence genetic risk factors implied in Autism Spectrum Disorders, with most mutations leading to CHD8 haploinsufficiency and the insurgence of specific phenotypes, such as macrocephaly, facial dysmorphisms, intellectual disability, and gastrointestinal complain...

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Autores principales:	Giulia Zarantonello, Michele Arnoldi, Michele Filosi, Toma Tebaldi, Giovanni Spirito, Anna Barbieri, Stefano Gustincich, Remo Sanges, Enrico Domenici, Francesca Di Leva, Marta Biagioli
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	autism spectrum disorders (ASD) CHD8 lncRNA natural antisense transcript (NAT) SINEUP post-transcriptional regulation Genetics QH426-470
Acceso en línea:	https://doaj.org/article/8aebf72ce5014c2fba54cc8dcf920ad9
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spelling	oai:doaj.org-article:8aebf72ce5014c2fba54cc8dcf920ad92021-11-30T10:05:08ZNatural SINEUP RNAs in Autism Spectrum Disorders: RAB11B-AS1 Dysregulation in a Neuronal CHD8 Suppression Model Leads to RAB11B Protein Increase1664-802110.3389/fgene.2021.745229https://doaj.org/article/8aebf72ce5014c2fba54cc8dcf920ad92021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fgene.2021.745229/fullhttps://doaj.org/toc/1664-8021CHD8 represents one of the highest confidence genetic risk factors implied in Autism Spectrum Disorders, with most mutations leading to CHD8 haploinsufficiency and the insurgence of specific phenotypes, such as macrocephaly, facial dysmorphisms, intellectual disability, and gastrointestinal complaints. While extensive studies have been conducted on the possible consequences of CHD8 suppression and protein coding RNAs dysregulation during neuronal development, the effects of transcriptional changes of long non-coding RNAs (lncRNAs) remain unclear. In this study, we focused on a peculiar class of natural antisense lncRNAs, SINEUPs, that enhance translation of a target mRNA through the activity of two RNA domains, an embedded transposable element sequence and an antisense region. By looking at dysregulated transcripts following CHD8 knock down (KD), we first identified RAB11B-AS1 as a potential SINEUP RNA for its domain configuration. Then we demonstrated that such lncRNA is able to increase endogenous RAB11B protein amounts without affecting its transcriptional levels. RAB11B has a pivotal role in vesicular trafficking, and mutations on this gene correlate with intellectual disability and microcephaly. Thus, our study discloses an additional layer of molecular regulation which is altered by CHD8 suppression. This represents the first experimental confirmation that naturally occurring SINEUP could be involved in ASD pathogenesis and underscores the importance of dysregulation of functional lncRNAs in neurodevelopment.Giulia ZarantonelloMichele ArnoldiMichele FilosiToma TebaldiToma TebaldiGiovanni SpiritoGiovanni SpiritoAnna BarbieriStefano GustincichRemo SangesRemo SangesEnrico DomeniciEnrico DomeniciFrancesca Di LevaMarta BiagioliFrontiers Media S.A.articleautism spectrum disorders (ASD)CHD8lncRNAnatural antisense transcript (NAT)SINEUPpost-transcriptional regulationGeneticsQH426-470ENFrontiers in Genetics, Vol 12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	autism spectrum disorders (ASD) CHD8 lncRNA natural antisense transcript (NAT) SINEUP post-transcriptional regulation Genetics QH426-470
spellingShingle	autism spectrum disorders (ASD) CHD8 lncRNA natural antisense transcript (NAT) SINEUP post-transcriptional regulation Genetics QH426-470 Giulia Zarantonello Michele Arnoldi Michele Filosi Toma Tebaldi Toma Tebaldi Giovanni Spirito Giovanni Spirito Anna Barbieri Stefano Gustincich Remo Sanges Remo Sanges Enrico Domenici Enrico Domenici Francesca Di Leva Marta Biagioli Natural SINEUP RNAs in Autism Spectrum Disorders: RAB11B-AS1 Dysregulation in a Neuronal CHD8 Suppression Model Leads to RAB11B Protein Increase
description	CHD8 represents one of the highest confidence genetic risk factors implied in Autism Spectrum Disorders, with most mutations leading to CHD8 haploinsufficiency and the insurgence of specific phenotypes, such as macrocephaly, facial dysmorphisms, intellectual disability, and gastrointestinal complaints. While extensive studies have been conducted on the possible consequences of CHD8 suppression and protein coding RNAs dysregulation during neuronal development, the effects of transcriptional changes of long non-coding RNAs (lncRNAs) remain unclear. In this study, we focused on a peculiar class of natural antisense lncRNAs, SINEUPs, that enhance translation of a target mRNA through the activity of two RNA domains, an embedded transposable element sequence and an antisense region. By looking at dysregulated transcripts following CHD8 knock down (KD), we first identified RAB11B-AS1 as a potential SINEUP RNA for its domain configuration. Then we demonstrated that such lncRNA is able to increase endogenous RAB11B protein amounts without affecting its transcriptional levels. RAB11B has a pivotal role in vesicular trafficking, and mutations on this gene correlate with intellectual disability and microcephaly. Thus, our study discloses an additional layer of molecular regulation which is altered by CHD8 suppression. This represents the first experimental confirmation that naturally occurring SINEUP could be involved in ASD pathogenesis and underscores the importance of dysregulation of functional lncRNAs in neurodevelopment.
format	article
author	Giulia Zarantonello Michele Arnoldi Michele Filosi Toma Tebaldi Toma Tebaldi Giovanni Spirito Giovanni Spirito Anna Barbieri Stefano Gustincich Remo Sanges Remo Sanges Enrico Domenici Enrico Domenici Francesca Di Leva Marta Biagioli
author_facet	Giulia Zarantonello Michele Arnoldi Michele Filosi Toma Tebaldi Toma Tebaldi Giovanni Spirito Giovanni Spirito Anna Barbieri Stefano Gustincich Remo Sanges Remo Sanges Enrico Domenici Enrico Domenici Francesca Di Leva Marta Biagioli
author_sort	Giulia Zarantonello
title	Natural SINEUP RNAs in Autism Spectrum Disorders: RAB11B-AS1 Dysregulation in a Neuronal CHD8 Suppression Model Leads to RAB11B Protein Increase
title_short	Natural SINEUP RNAs in Autism Spectrum Disorders: RAB11B-AS1 Dysregulation in a Neuronal CHD8 Suppression Model Leads to RAB11B Protein Increase
title_full	Natural SINEUP RNAs in Autism Spectrum Disorders: RAB11B-AS1 Dysregulation in a Neuronal CHD8 Suppression Model Leads to RAB11B Protein Increase
title_fullStr	Natural SINEUP RNAs in Autism Spectrum Disorders: RAB11B-AS1 Dysregulation in a Neuronal CHD8 Suppression Model Leads to RAB11B Protein Increase
title_full_unstemmed	Natural SINEUP RNAs in Autism Spectrum Disorders: RAB11B-AS1 Dysregulation in a Neuronal CHD8 Suppression Model Leads to RAB11B Protein Increase
title_sort	natural sineup rnas in autism spectrum disorders: rab11b-as1 dysregulation in a neuronal chd8 suppression model leads to rab11b protein increase
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/8aebf72ce5014c2fba54cc8dcf920ad9
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Natural SINEUP RNAs in Autism Spectrum Disorders: RAB11B-AS1 Dysregulation in a Neuronal CHD8 Suppression Model Leads to RAB11B Protein Increase

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