A natural antisense transcript at the Huntington's disease repeat locus regulates HTT expression

被引：150
作者：
Chung, Daniel W. [1 ]
Rudnicki, Dobrila D. [1 ]
Yu, Lan [1 ]
Margolis, Russell L. [1 ,2 ,3 ]
机构：
[1] Johns Hopkins Univ, Lab Genet Neurobiol, Dept Psychiat, Div Neurobiol,Sch Med, Baltimore, MD 21287 USA
[2] Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21287 USA
[3] Johns Hopkins Univ, Sch Med, Program Cellular & Mol Med, Baltimore, MD 21287 USA
来源：
HUMAN MOLECULAR GENETICS | 2011年 / 20卷 / 17期
基金：
美国国家卫生研究院;
关键词：
CYSTATIN B GENE; PROGRESSIVE MYOCLONUS EPILEPSY; FRAGILE-X-SYNDROME; MYOTONIC-DYSTROPHY; BINDING SITES; HD GENE; EXPANSION; RNA; PROMOTER; ATAXIA;
D O I：
10.1093/hmg/ddr263
中图分类号：
Q5 [生物化学]; Q7 [分子生物学];
学科分类号：
071010 ; 081704 ;
摘要：
Huntington's disease (HD) is a progressive neurodegenerative disorder caused by a CAG repeat expansion in exon 1 of huntingtin (HTT). Relatively little attention has been directed to the genomic features of the antisense strand at the HD locus, though the presence of a transcript from this strand has been suggested by a survey of the entire transcriptome and the existence of several EST tags. In this study, we identified huntingtin antisense (HTTAS), a natural antisense transcript at the HD repeat locus that contain the repeat tract. HTTAS is 5' capped, poly (A) tailed and contains three exons, alternatively spliced into HTTAS_v1 (exons 1 and 3) and HTTAS_v2 (exons 2 and 3). Exon 1 includes the repeat. HTTAS_v1 has a weak promoter, and is expressed at low levels in multiple tissue types and throughout the brain. Reporter assays indicate that while efficient promoter activity requires a short repeat, repeat expansion reduces promoter efficiency. Consistent with the reporter assays, levels of HTTAS_v1 are reduced in human HD frontal cortex. In cell systems, overexpression of HTTAS_v1 specifically reduces endogenous HTT transcript levels, while siRNA knockdown of HTTAS_v1 increases HTT transcript levels. Minigene constructs of the HD locus confirm the regulatory effect of HTTAS_v1 on HTT, and demonstrate that the effect is dependent on repeat length and is at least partially Dicer dependent. Together, these findings provide strong evidence for the existence of a gene antisense to HTT, with properties that include regulation of HTT expression.
引用
收藏
页码：3467 / 3477
页数：11
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