Changes in expression of the long non-coding RNA FMR4 associate with altered gene expression during differentiation of human neural precursor cells.
Changes in expression of the long non-coding RNA FMR4 associate with altered gene expression during differentiation of human neural precursor cells.
复制标题
在人神经前体细胞分化过程中，长的非编码RNA FMR4的表达变化与基因表达改变。
DOI：
10.3389/fgene.2015.00263
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发表时间：
2015
影响因子：
3.7
通讯作者：
Wahlestedt C
中科院分区：
文献类型：
--
作者：
Peschansky VJ;Pastori C;Zeier Z;Motti D;Wentzel K;Velmeshev D;Magistri M;Bixby JL;Lemmon VP;Silva JP;Wahlestedt C
脆性X染色体智力低下1（FMR 1）基因中的CGG重复扩增导致一个相关疾病家族，其特征在于智力残疾和自闭症脆性X综合征（FXS），或成人发作的神经变性脆性X相关震颤/共济失调综合征。然而，FMR 1基因座是复杂的，编码几个长的非编码RNA，其表达被重复扩增突变改变。到目前为止，这些lncRNA的作用尚不清楚;因此，我们研究了我们先前鉴定的FMR 4的功能。FMR 1三联体重复序列的“全长”扩增导致FMR 1和FMR 4的沉默，因此我们对可能增加FXS表型表现的潜在功能丧失感兴趣。由于这两个转录本不表现出彼此的顺式调节，我们使用基因表达微阵列研究了FMR 4在远端基因组位点调节靶基因的潜力。我们鉴定了FMR 4应答基因，包括甲基-CpG结合结构域蛋白4（MBD 4）。此外，我们发现，在分化的人神经前体细胞中，FMR 4的表达与FMR 1（预计与FMR 4共享双向启动子）和MBD 4的表达相反，受到发育调控。因此，我们认为FMR 4的功能是作为一种基因调控lncRNA，这种转录本可能在正常发育中发挥作用。对FMR 4的进一步研究增加了我们对调控lncRNA的作用和FMR 1重复扩增的后果的理解。
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.