Alterations in mRNA 3′ UTR Isoform Abundance Accompany Gene Expression Changes in Human Huntington’s Disease Brains

Romo, Lindsay; Ashar-Patel, Ami; Pfister, Edith L.; Aronin, Neil

doi:10.1016/j.celrep.2017.09.009

Cited by 44 publications

(48 citation statements)

References 61 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Interestingly, in our study the level of the shortened HTT transcript did not change, suggesting that the transcript may be NMD-resistant. The HTT gene contains 67 exons and has three isoforms of mRNA transcripts (Romo et al, 2017 ); the two predominant forms are 10,366 and of 13,711 bp (Lin et al, 1993 ). The longer transcript differs by an additional 3′ UTR sequence of 3,360 bp that affects mRNA localization, stability, and translation (Di Giammartino et al, 2011 ).…”

Section: Discussionmentioning

confidence: 99%

Precise Excision of the CAG Tract from the Huntingtin Gene by Cas9 Nickases

et al. 2018

View full text Add to dashboard Cite

Huntington's disease (HD) is a progressive autosomal dominant neurodegenerative disorder caused by the expansion of CAG repeats in the first exon of the huntingtin gene (HTT). The accumulation of polyglutamine-rich huntingtin proteins affects various cellular functions and causes selective degeneration of neurons in the striatum. Therapeutic strategies used to date to silence the expression of mutant HTT include antisense oligonucleotides, RNA interference-based approaches and, recently, genome editing with the CRISPR/Cas9 system. Here, we demonstrate that the CAG repeat tract can be precisely excised from the HTT gene with the use of the paired Cas9 nickase strategy. As a model, we used HD patient-derived fibroblasts with varied numbers of CAG repeats. The repeat excision inactivated the HTT gene and abrogated huntingtin synthesis in a CAG repeat length-independent manner. Because Cas9 nickases are known to be safe and specific, our approach provides an attractive treatment tool for HD that can be extended to other polyQ disorders.

show abstract

Section: Discussionmentioning

confidence: 99%

Precise Excision of the CAG Tract from the Huntingtin Gene by Cas9 Nickases

et al. 2018

View full text Add to dashboard Cite

show abstract

“…Moreover, knockdown of CNOT6 (CCR4-NOT transcription complex subunit 6) RBP leads to HTT mRNA isoform changes similar to those found in the HD motor cortex. These results indicate that the expression of different 3′-UTR isoforms from a distinct group of genes including HTT is one of the molecular features in the HD ( Table 1 ) [ 51 ].…”

Section: Neurological Diseasesmentioning

confidence: 99%

Alternative Polyadenylation in Human Diseases

2017

View full text Add to dashboard Cite

Varying length of messenger RNA (mRNA) 3′-untranslated region is generated by alternating the usage of polyadenylation sites during pre-mRNA processing. It is prevalent through all eukaryotes and has emerged as a key mechanism for controlling gene expression. Alternative polyadenylation (APA) plays an important role for cell growth, proliferation, and differentiation. In this review, we discuss the functions of APA related with various physiological conditions including cellular metabolism, mRNA processing, and protein diversity in a variety of disease models. We also discuss the molecular mechanisms underlying APA regulation, such as variations in the concentration of mRNA processing factors and RNA-binding proteins, as well as global transcriptome changes under cellular signaling pathway.

show abstract

“…The mutation is a CAG repeat expansion in exon 1 of the huntingtin gene ( HTT ) 2 , which translates to a polyglutamine (polyQ) track in the huntingtin protein (HTT). In addition to the three full length isoforms 3 – 5 , other isoforms consisting of a combination of the inclusion of cryptic exons 6 , 7 , retention of parts of introns and alternative splice site usages 7 – 9 have been identified. However, these isoforms are subject to nonsense mediated RNA decay and will have no functional consequences.…”

Section: Introductionmentioning

confidence: 99%

Regulatory mechanisms of incomplete huntingtin mRNA splicing

et al. 2018

View full text Add to dashboard Cite

Huntington’s disease is caused by a CAG repeat expansion in exon 1 of the HTT gene. We have previously shown that exon 1 HTT does not always splice to exon 2 producing a small transcript (HTTexon1) that encodes the highly pathogenic exon 1 HTT protein. The mechanisms by which this incomplete splicing occurs are unknown. Here, we have generated a minigene system that recapitulates the CAG repeat-length dependence of HTTexon1 production, and has allowed us to define the regions of intron 1 necessary for incomplete splicing. We show that manipulation of the expression levels of the splicing factor SRSF6, predicted to bind CAG repeats, modulates this aberrant splicing event and also demonstrate that RNA polymerase II transcription speed regulates the levels of HTTexon1 production. Understanding the mechanisms by which this pathogenic exon 1 HTT is generated may provide the basis for the development of strategies to prevent its production.

show abstract

Alterations in mRNA 3′ UTR Isoform Abundance Accompany Gene Expression Changes in Human Huntington’s Disease Brains

Cited by 44 publications

References 61 publications

Precise Excision of the CAG Tract from the Huntingtin Gene by Cas9 Nickases

Precise Excision of the CAG Tract from the Huntingtin Gene by Cas9 Nickases

Alternative Polyadenylation in Human Diseases

Regulatory mechanisms of incomplete huntingtin mRNA splicing

Contact Info

Product

Resources

About