title: The long non-coding RNA FMR4 promotes proliferation of human neural precursor cells and epigenetic regulation of gene expression in trans.
abstract: Triplet repeat expansions in the Fragile X mental retardation 1 (FMR1) gene cause either intellectual disability and autism, or adult-onset neurodegeneration, with poorly understood variability in presentation. Previous studies have identified several long noncoding RNAs (lncRNAs) at the FMR1 locus, including FMR4. Similarly to FMR1, FMR4 is silenced by large-repeat expansions that result in enrichment of DNA and histone methylation within the shared promoter and repeat sequence, suggesting a possible role for this noncoding RNA in the pathophysiology of Fragile X. We therefore assessed the functional role of FMR4 to gain further insight into the molecular processes in Fragile X-associated disorders. Previous work showed that FMR4 does not exhibit cis-regulation of FMR1. Here, we found that FMR4 is a chromatin-associated transcript and, using genome-wide chromatin immunoprecipitation experiments, showed that FMR4 alters the chromatin state and the expression of several hundred genes in trans. Among the genes regulated by FMR4, we found enrichment for those involved in neural development and cellular proliferation. S-phase marker assays further demonstrated that FMR4 may promote cellular proliferation, rather than differentiation, of human neural precursor cells (hNPCs). By establishing this novel function for FMR4 in hNPCs, we lend support to existing evidence of the epigenetic involvement of lncRNA in nervous system development, and increase our understanding of the complex pathogenesis underlying neurological disorders associated with FMR1 repeat expansions.
authors.affiliation: Center for Therapeutic Innovation and Department of Psychiatry and Behavioral Sciences, University of Miami Miller School of Medicine, 1501 NW 10th Ave, Biomedical Research Building (M-860), Miami, FL 33136, USA. Electronic address: vpeschansky@med.miami.edu.
authors.forename: Veronica J
authors.initials: VJ
authors.lastname: Peschansky
authors.affiliation: Center for Therapeutic Innovation and Department of Psychiatry and Behavioral Sciences, University of Miami Miller School of Medicine, 1501 NW 10th Ave, Biomedical Research Building (M-860), Miami, FL 33136, USA. Electronic address: cpastori@med.miami.edu.
authors.forename: Chiara
authors.initials: C
authors.lastname: Pastori
authors.affiliation: Center for Therapeutic Innovation and Department of Psychiatry and Behavioral Sciences, University of Miami Miller School of Medicine, 1501 NW 10th Ave, Biomedical Research Building (M-860), Miami, FL 33136, USA. Electronic address: zzeier@med.miami.edu.
authors.forename: Zane
authors.initials: Z
authors.lastname: Zeier
authors.affiliation: Center for Therapeutic Innovation and Department of Psychiatry and Behavioral Sciences, University of Miami Miller School of Medicine, 1501 NW 10th Ave, Biomedical Research Building (M-860), Miami, FL 33136, USA. Electronic address: k.wentzel1@umiami.edu.
authors.forename: Katya
authors.initials: K
authors.lastname: Wentzel
authors.affiliation: Center for Therapeutic Innovation and Department of Psychiatry and Behavioral Sciences, University of Miami Miller School of Medicine, 1501 NW 10th Ave, Biomedical Research Building (M-860), Miami, FL 33136, USA. Electronic address: dvelmeshev@med.miami.edu.
authors.forename: Dmitry
authors.initials: D
authors.lastname: Velmeshev
authors.affiliation: Center for Therapeutic Innovation and Department of Psychiatry and Behavioral Sciences, University of Miami Miller School of Medicine, 1501 NW 10th Ave, Biomedical Research Building (M-860), Miami, FL 33136, USA. Electronic address: mmagistri@med.miami.edu.
authors.forename: Marco
authors.initials: M
authors.lastname: Magistri
authors.affiliation: Center for Therapeutic Innovation and Department of Psychiatry and Behavioral Sciences, University of Miami Miller School of Medicine, 1501 NW 10th Ave, Biomedical Research Building (M-860), Miami, FL 33136, USA. Electronic address: jsilva3@med.miami.edu.
authors.forename: José P
authors.initials: JP
authors.lastname: Silva
authors.affiliation: Center for Therapeutic Innovation and Department of Psychiatry and Behavioral Sciences, University of Miami Miller School of Medicine, 1501 NW 10th Ave, Biomedical Research Building (M-860), Miami, FL 33136, USA. Electronic address: cwahlestedt@med.miami.edu.
authors.forename: Claes
authors.initials: C
authors.lastname: Wahlestedt
mesh_terms: D049109:Cell Proliferation; D002478:Cells, Cultured; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism* / Q000502:physiology; D044127:Epigenesis, Genetic; D018507:Gene Expression Regulation, Developmental; D050437:Genes, Developmental; D057809:HEK293 Cells; D006801:Humans; D058953:Neural Stem Cells / Q000166:cytology / Q000378:metabolism* / Q000502:physiology; D055495:Neurogenesis; D062085:RNA, Long Noncoding / Q000235:genetics* / Q000378:metabolism
chemical_list: D062085:RNA, Long Noncoding; C000613323:long non-coding RNA FMR4, human
keywords: Cellular proliferation; Chromatin modification; Epigenetics; Fragile X; Intellectual disability; Neurodevelopment; lncRNA