Changes in expression of the long non-coding RNA FMR4 associate with altered gene expression during differentiation of human neural precursor cells

Veronica J. Peschansky, Chiara Pastori, Zane R Zeier, Dario Motti, Katya Wentzel, Dmitry Velmeshev, Marco Magistri, John Bixby, Vance Lemmon, José P. Silva, Claes R Wahlestedt

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

CGG repeat expansions in the Fragile X mental retardation 1 (FMR1) gene are responsible for a family of associated disorders characterized by either intellectual disability and autism Fragile X Syndrome (FXS), or adult-onset neurodegeneration Fragile X-associated Tremor/Ataxia Syndrome. However, the FMR1 locus is complex and encodes several long non-coding RNAs, whose expression is altered by repeat expansion mutations. The role of these lncRNAs is thus far unknown; therefore we investigated the functionality of FMR4, which we previously identified. "Full"-length expansions of the FMR1 triplet repeat cause silencing of both FMR1 and FMR4, thus we are interested in potential loss-of-function that may add to phenotypic manifestation of FXS. Since the two transcripts do not exhibit cis-regulation of one another, we examined the potential for FMR4 to regulate target genes at distal genomic loci using gene expression microarrays. We identified FMR4-responsive genes, including the methyl-CpG-binding domain protein 4 (MBD4). Furthermore, we found that in differentiating human neural precursor cells, FMR4 expression is developmentally regulated in opposition to expression of both FMR1 (which is expected to share a bidirectional promoter with FMR4) and MBD4. We therefore propose that FMR4's function is as a gene-regulatory lncRNA and that this transcript may function in normal development. Closer examination of FMR4 increases our understanding of the role of regulatory lncRNA and the consequences of FMR1 repeat expansions.

Original languageEnglish (US)
Article number263
JournalFrontiers in Genetics
Volume6
Issue numberAug
DOIs
StatePublished - 2015

Fingerprint

Long Noncoding RNA
Intellectual Disability
Gene Expression
Fragile X Syndrome
Carrier Proteins
Genes
Trinucleotide Repeats
Regulator Genes
Autistic Disorder
Mutation

Keywords

  • Chromatin remodeling
  • Differentiation
  • Epigenetics
  • FMR4 Fragile X
  • Intellectual disability
  • lncRNA
  • MBD4

ASJC Scopus subject areas

  • Genetics
  • Molecular Medicine
  • Genetics(clinical)

Cite this

Changes in expression of the long non-coding RNA FMR4 associate with altered gene expression during differentiation of human neural precursor cells. / Peschansky, Veronica J.; Pastori, Chiara; Zeier, Zane R; Motti, Dario; Wentzel, Katya; Velmeshev, Dmitry; Magistri, Marco; Bixby, John; Lemmon, Vance; Silva, José P.; Wahlestedt, Claes R.

In: Frontiers in Genetics, Vol. 6, No. Aug, 263, 2015.

Research output: Contribution to journalArticle

Peschansky, Veronica J. ; Pastori, Chiara ; Zeier, Zane R ; Motti, Dario ; Wentzel, Katya ; Velmeshev, Dmitry ; Magistri, Marco ; Bixby, John ; Lemmon, Vance ; Silva, José P. ; Wahlestedt, Claes R. / Changes in expression of the long non-coding RNA FMR4 associate with altered gene expression during differentiation of human neural precursor cells. In: Frontiers in Genetics. 2015 ; Vol. 6, No. Aug.
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abstract = "CGG repeat expansions in the Fragile X mental retardation 1 (FMR1) gene are responsible for a family of associated disorders characterized by either intellectual disability and autism Fragile X Syndrome (FXS), or adult-onset neurodegeneration Fragile X-associated Tremor/Ataxia Syndrome. However, the FMR1 locus is complex and encodes several long non-coding RNAs, whose expression is altered by repeat expansion mutations. The role of these lncRNAs is thus far unknown; therefore we investigated the functionality of FMR4, which we previously identified. {"}Full{"}-length expansions of the FMR1 triplet repeat cause silencing of both FMR1 and FMR4, thus we are interested in potential loss-of-function that may add to phenotypic manifestation of FXS. Since the two transcripts do not exhibit cis-regulation of one another, we examined the potential for FMR4 to regulate target genes at distal genomic loci using gene expression microarrays. We identified FMR4-responsive genes, including the methyl-CpG-binding domain protein 4 (MBD4). Furthermore, we found that in differentiating human neural precursor cells, FMR4 expression is developmentally regulated in opposition to expression of both FMR1 (which is expected to share a bidirectional promoter with FMR4) and MBD4. We therefore propose that FMR4's function is as a gene-regulatory lncRNA and that this transcript may function in normal development. Closer examination of FMR4 increases our understanding of the role of regulatory lncRNA and the consequences of FMR1 repeat expansions.",
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AU - Peschansky, Veronica J.

AU - Pastori, Chiara

AU - Zeier, Zane R

AU - Motti, Dario

AU - Wentzel, Katya

AU - Velmeshev, Dmitry

AU - Magistri, Marco

AU - Bixby, John

AU - Lemmon, Vance

AU - Silva, José P.

AU - Wahlestedt, Claes R

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N2 - CGG repeat expansions in the Fragile X mental retardation 1 (FMR1) gene are responsible for a family of associated disorders characterized by either intellectual disability and autism Fragile X Syndrome (FXS), or adult-onset neurodegeneration Fragile X-associated Tremor/Ataxia Syndrome. However, the FMR1 locus is complex and encodes several long non-coding RNAs, whose expression is altered by repeat expansion mutations. The role of these lncRNAs is thus far unknown; therefore we investigated the functionality of FMR4, which we previously identified. "Full"-length expansions of the FMR1 triplet repeat cause silencing of both FMR1 and FMR4, thus we are interested in potential loss-of-function that may add to phenotypic manifestation of FXS. Since the two transcripts do not exhibit cis-regulation of one another, we examined the potential for FMR4 to regulate target genes at distal genomic loci using gene expression microarrays. We identified FMR4-responsive genes, including the methyl-CpG-binding domain protein 4 (MBD4). Furthermore, we found that in differentiating human neural precursor cells, FMR4 expression is developmentally regulated in opposition to expression of both FMR1 (which is expected to share a bidirectional promoter with FMR4) and MBD4. We therefore propose that FMR4's function is as a gene-regulatory lncRNA and that this transcript may function in normal development. Closer examination of FMR4 increases our understanding of the role of regulatory lncRNA and the consequences of FMR1 repeat expansions.

AB - CGG repeat expansions in the Fragile X mental retardation 1 (FMR1) gene are responsible for a family of associated disorders characterized by either intellectual disability and autism Fragile X Syndrome (FXS), or adult-onset neurodegeneration Fragile X-associated Tremor/Ataxia Syndrome. However, the FMR1 locus is complex and encodes several long non-coding RNAs, whose expression is altered by repeat expansion mutations. The role of these lncRNAs is thus far unknown; therefore we investigated the functionality of FMR4, which we previously identified. "Full"-length expansions of the FMR1 triplet repeat cause silencing of both FMR1 and FMR4, thus we are interested in potential loss-of-function that may add to phenotypic manifestation of FXS. Since the two transcripts do not exhibit cis-regulation of one another, we examined the potential for FMR4 to regulate target genes at distal genomic loci using gene expression microarrays. We identified FMR4-responsive genes, including the methyl-CpG-binding domain protein 4 (MBD4). Furthermore, we found that in differentiating human neural precursor cells, FMR4 expression is developmentally regulated in opposition to expression of both FMR1 (which is expected to share a bidirectional promoter with FMR4) and MBD4. We therefore propose that FMR4's function is as a gene-regulatory lncRNA and that this transcript may function in normal development. Closer examination of FMR4 increases our understanding of the role of regulatory lncRNA and the consequences of FMR1 repeat expansions.

KW - Chromatin remodeling

KW - Differentiation

KW - Epigenetics

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KW - Intellectual disability

KW - lncRNA

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