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J Cell Mol Med. 2017 Nov;21(11):2974-2984. doi: 10.1111/jcmm.13209. Epub 2017 May 19.

Modulation of nuclear REST by alternative splicing: a potential therapeutic target for Huntington's disease.

Chen GL1,2,3, Ma Q4, Goswami D5,6,7, Shang J1, Miller GM1,8.

Author information

1
Department of Pharmaceutical Sciences and Center for Drug Discovery, School of Pharmacy, Northeastern University, Boston, MA, USA.
2
Guangxi Collaborative Innovation Center for Biomedicine, Guangxi Medical University, Nanning, Guangxi, China.
3
Research Center for Regenerative Medicine of Guangxi, Guangxi Medical University, Nanning, Guangxi, China.
4
Department of Psychiatry, Institute for Human Performance, SUNY Upstate Medical University, Syracuse, NY, USA.
5
Center for the Study of Traumatic Encephalopathy, Boston University School of Medicine, Boston, MA, USA.
6
Department of Neurology, Boston University School of Medicine, Boston, MA, USA.
7
VA Boston HealthCare System, Boston, MA, USA.
8
Department of Chemical Engineering, School of Engineering, Northeastern University, Boston, MA, USA.

Abstract

Huntington's disease (HD) is caused by a genetically mutated huntingtin (mHtt) protein with expanded polyQ stretch, which impairs cytosolic sequestration of the repressor element-1 silencing transcription factor (REST), resulting in excessive nuclear REST and subsequent repression of neuronal genes. We recently demonstrated that REST undergoes extensive, context-dependent alternative splicing, of which exon-3 skipping (∆E3 )-a common event in human and nonhuman primates-causes loss of a motif critical for REST nuclear targeting. This study aimed to determine whether ∆E3 can be targeted to reduce nuclear REST and rescue neuronal gene expression in mouse striatal-derived, mHtt-expressing STHdhQ111/Q111 cells-a well-established cellular model of HD. We designed two morpholino antisense oligos (ASOs) targeting the splice sites of Rest E3 and examined their effects on ∆E3 , nuclear Rest accumulation and Rest-controlled gene expression in STHdhQ111/Q111 cells. We found that (1) the ASOs treatment significantly induced ∆E3 , reduced nuclear Rest, and rescued transcription and/or mis-splicing of specific neuronal genes (e.g. Syn1 and Stmn2) in STHdhQ111/Q111 cells; and (2) the ASOs-induced transcriptional regulation was dependent on ∆E3 induction and mimicked by siRNA-mediated knock-down of Rest expression. Our findings demonstrate modulation of nuclear REST by ∆E3 and its potential as a new therapeutic target for HD and provide new insights into environmental regulation of genome function and pathogenesis of HD. As ∆E3 is modulated by cellular signalling and linked to various types of cancer, we anticipate that ∆E3 contributes to environmentally tuned REST function and may have a broad range of clinical implications.

KEYWORDS:

Huntington's disease; PPARγ; REST/NRSF; Stmn2; Syn-1; alternative splicing; antisense oligos; gene therapy; nuclear translocation

PMID:
28524599
PMCID:
PMC5661251
DOI:
10.1111/jcmm.13209
[Indexed for MEDLINE]
Free PMC Article

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