Role of CTCF protein in regulating FMR1 locus transcription.
Role of CTCF protein in regulating FMR1 locus transcription.
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DOI：
10.1371/journal.pgen.1003601
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发表时间：
2013
期刊：
影响因子：
4.5
通讯作者：
Neri G
中科院分区：
文献类型：
--
作者：
Lanni S;Goracci M;Borrelli L;Mancano G;Chiurazzi P;Moscato U;Ferrè F;Helmer-Citterich M;Tabolacci E;Neri G
Fragile X syndrome (FXS), the leading cause of inherited intellectual disability, is caused by epigenetic silencing of the FMR1 gene, through expansion and methylation of a CGG triplet repeat (methylated full mutation). An antisense transcript (FMR1-AS1), starting from both promoter and intron 2 of the FMR1 gene, was demonstrated in transcriptionally active alleles, but not in silent FXS alleles. Moreover, a DNA methylation boundary, which is lost in FXS, was recently identified upstream of the FMR1 gene. Several nuclear proteins bind to this region, like the insulator protein CTCF. Here we demonstrate for the first time that rare unmethylated full mutation (UFM) alleles present the same boundary described in wild type (WT) alleles and that CTCF binds to this region, as well as to the FMR1 gene promoter, exon 1 and intron 2 binding sites. Contrariwise, DNA methylation prevents CTCF binding to FXS alleles. Drug-induced CpGs demethylation does not restore this binding. CTCF knock-down experiments clearly established that CTCF does not act as insulator at the active FMR1 locus, despite the presence of a CGG expansion. CTCF depletion induces heterochromatinic histone configuration of the FMR1 locus and results in reduction of FMR1 transcription, which however is not accompanied by spreading of DNA methylation towards the FMR1 promoter. CTCF depletion is also associated with FMR1-AS1 mRNA reduction. Antisense RNA, like sense transcript, is upregulated in UFM and absent in FXS cells and its splicing is correlated to that of the FMR1-mRNA. We conclude that CTCF has a complex role in regulating FMR1 expression, probably through the organization of chromatin loops between sense/antisense transcriptional regulatory regions, as suggested by bioinformatics analysis. Fragile X syndrome is the most common cause of inherited intellectual disability, accounting for about 1∶3000 males and 1∶4000 females. It is caused by a dynamic mutation of FMR1, a gene mapping on the X chromosome and containing a CGG repeat in its promoter region. Expansion of this unstable sequence beyond 200 repeats (full mutation) is followed by DNA methylation and histone changes, leading to the transcriptional inactivation of FMR1 and to the lack of the FMRP protein. Recently, an antisense transcript (FMR1-AS1) spanning the CGG repeats and a region of transition of DNA methylation (boundary) located upstream of the CGG repeats have been identified in transcriptional active FMR1 alleles. Several nuclear proteins bound to the methylation boundary have been described, such as the zinc-finger protein CTCF, the first known insulator in mammals. This protein is an important transcriptional regulator of genes harboring trinucleotide repeats and it is mostly active in chromatin organization. For the first time, we have investigated the role of CTCF protein in the transcriptional regulation of the FMR1 gene. Our results define a complex role for CTCF acting through chromatin organization of the FMR1 locus.
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影响因子：
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作者：
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DOI：
10.1073/pnas.0605343103
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