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RNA activation of haploinsufficient Foxg1 gene in murine neocortex
Cristina Fimiani1, Elisa Goina1, Qin Su2
1Lab of Cerebral Cortex Development, SISSA, via Bonomea 265 - 34136 Trieste, Italy.
Abstract:
More than one hundred distinct gene hemizygosities are specifically linked to epilepsy, mental retardation, autism, schizophrenia and neuro-degeneration. Radical repair of these gene deficits via genome engineering is hardly feasible. The same applies to therapeutic stimulation of the spared allele by artificial transactivators. Small activating RNAs (saRNAs) offer an alternative, appealing approach. As a proof-of-principle, here we tested this approach on the Rett syndrome-linked, haploinsufficient, Foxg1 brain patterning gene. We selected a set of artificial small activating RNAs (saRNAs) upregulating it in neocortical precursors and their derivatives. Expression of these effectors achieved a robust biological outcome. saRNA-driven activation (RNAa) was limited to neural cells which normally express Foxg1 and did not hide endogenous gene tuning. saRNAs recognized target chromatin through a ncRNA stemming from it. Gene upregulation required Ago1 and was associated to RNApolII enrichment throughout the Foxg1 locus. Finally, saRNA delivery to murine neonatal brain replicated Foxg1-RNAa in vivo.
Insights
Small activating RNAs (saRNAs) offer a novel gene therapy approach for neurological disorders. This study demonstrates saRNAs can upregulate the Foxg1 gene in brain cells, showing promise for treating conditions like Rett syndrome.
Area of Science:
- Neuroscience
- Genetics
- Molecular Biology
Background:
- Over 100 gene hemizygosities are linked to neurological disorders like epilepsy, autism, and neurodegeneration.
- Current gene repair and artificial transactivator methods are not feasible for these deficits.
Purpose of the Study:
- To investigate the potential of small activating RNAs (saRNAs) as a therapeutic strategy for gene haploinsufficiency.
- To demonstrate the efficacy of saRNA-mediated gene activation (RNAa) for the Foxg1 gene, linked to Rett syndrome.
Main Methods:
- Designed and selected artificial saRNAs to upregulate the haploinsufficient Foxg1 gene.
- Tested saRNA efficacy in neocortical precursors and their derivatives.
- Delivered saRNAs to neonatal mouse brains to assess in vivo effects.
Main Results:
- saRNA-mediated activation (RNAa) robustly upregulated Foxg1 expression in neural cells.
- RNAa was specific to endogenous Foxg1 expression patterns and did not interfere with gene tuning.
- Upregulation required Ago1 and was associated with RNA polymerase II enrichment at the Foxg1 locus.
- In vivo delivery to neonatal mouse brains successfully replicated Foxg1-RNAa.
Conclusions:
- saRNAs represent a promising, feasible approach for addressing gene deficits in neurological conditions.
- RNAa offers a targeted method for gene upregulation, with potential applications in treating Rett syndrome and other neurodevelopmental disorders.
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