title: RNA activation of haploinsufficient Foxg1 gene in murine neocortex.
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.
authors.affiliation: Lab of Cerebral Cortex Development, SISSA, via Bonomea 265 - 34136 Trieste, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Fimiani
authors.affiliation: Lab of Cerebral Cortex Development, SISSA, via Bonomea 265 - 34136 Trieste, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Goina
authors.affiliation: Viral Vector Core, University of Massachusetts Medical School - 368 Plantation Street, AS6-2049 - Worcester, MA 01605, USA.
authors.forename: Qin
authors.initials: Q
authors.lastname: Su
authors.affiliation: Viral Vector Core, University of Massachusetts Medical School - 368 Plantation Street, AS6-2049 - Worcester, MA 01605, USA.|Horae Gene Therapy Center, University of Massachusetts Medical School - 368 Plantation Street, AS6-2049 - Worcester, MA 01605, USA.|Department of Microbiology and Physiological Systems, University of Massachusetts Medical School - 368 Plantation Street, AS6-2049 - Worcester, MA 01605, USA.
authors.forename: Guangping
authors.initials: G
authors.lastname: Gao
authors.affiliation: Lab of Cerebral Cortex Development, SISSA, via Bonomea 265 - 34136 Trieste, Italy.
authors.forename: Antonello
authors.initials: A
authors.lastname: Mallamaci
mesh_terms: D016475:3T3 Cells; D000818:Animals; D060565:Argonaute Proteins / Q000235:genetics*; D002460:Cell Line; D039642:Eukaryotic Initiation Factors / Q000235:genetics*; D051858:Forkhead Transcription Factors / Q000235:genetics*; D057809:HEK293 Cells; D057895:Haploinsufficiency / Q000235:genetics*; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D019579:Neocortex / Q000378:metabolism*; D009417:Nerve Tissue / Q000254:growth & development; D009419:Nerve Tissue Proteins / Q000235:genetics*; D034622:RNA Interference; D012320:RNA Polymerase III / Q000235:genetics*; D034741:RNA, Small Interfering / Q000235:genetics; D015518:Rett Syndrome / Q000235:genetics / Q000628:therapy; D015533:Transcriptional Activation / Q000235:genetics*; D015854:Up-Regulation / Q000235:genetics
chemical_list: C549050:Ago1 protein, mouse; D060565:Argonaute Proteins; D039642:Eukaryotic Initiation Factors; D051858:Forkhead Transcription Factors; C489565:Foxg1 protein, mouse; D035683:MicroRNAs; D009419:Nerve Tissue Proteins; D034741:RNA, Small Interfering; D012320:RNA Polymerase III