Cross-talking noncoding RNAs contribute to cell-specific neurodegeneration in SCA7

Jennifer Y Tan; Keith W Vance; Miguel A Varela; Tamara Sirey; Lauren M Watson; Helen J Curtis; Martina Marinello; Sandro Alves; Bruno R Steinkraus; Sarah Cooper; Tatyana Nesterova; Neil Brockdorff; Tudor A Fulga; Alexis Brice; Annie Sittler; Peter L Oliver; Matthew J Wood; Chris P Ponting; Ana C Marques

doi:10.1038/nsmb.2902

Cross-talking noncoding RNAs contribute to cell-specific neurodegeneration in SCA7

Jennifer Y Tan, Keith W Vance, Miguel A Varela, Tamara Sirey, Lauren M Watson, Helen J Curtis, Martina Marinello, Sandro Alves, Bruno R Steinkraus, Sarah Cooper, Tatyana Nesterova, Neil Brockdorff, Tudor A Fulga, Alexis Brice, Annie Sittler, Peter L Oliver, Matthew J Wood, Chris P Ponting, Ana C Marques

Department of Life Sciences

Research output: Contribution to journal › Article › peer-review

74 Citations (SciVal)

Abstract

What causes the tissue-specific pathology of diseases resulting from mutations in housekeeping genes? Specifically, in spinocerebellar ataxia type 7 (SCA7), a neurodegenerative disorder caused by a CAG-repeat expansion in ATXN7 (which encodes an essential component of the mammalian transcription coactivation complex, STAGA), the factors underlying the characteristic progressive cerebellar and retinal degeneration in patients were unknown. We found that STAGA is required for the transcription initiation of miR-124, which in turn mediates the post-transcriptional cross-talk between lnc-SCA7, a conserved long noncoding RNA, and ATXN7 mRNA. In SCA7, mutations in ATXN7 disrupt these regulatory interactions and result in a neuron-specific increase in ATXN7 expression. Strikingly, in mice this increase is most prominent in the SCA7 disease-relevant tissues, namely the retina and cerebellum. Our results illustrate how noncoding RNA-mediated feedback regulation of a ubiquitously expressed housekeeping gene may contribute to specific neurodegeneration.

Original language	English
Pages (from-to)	955-961
Number of pages	7
Journal	Nature Structural and Molecular Biology
Volume	21
Issue number	11
Early online date	12 Oct 2014
DOIs	https://doi.org/10.1038/nsmb.2902
Publication status	Published - 1 Nov 2014

Keywords

Animals
Cell Line, Tumor
Cerebellum
Feedback, Physiological
Female
Fibroblasts
Gene Expression Profiling
Gene Expression Regulation
Humans
Male
Mice
MicroRNAs
Mutation
Nerve Tissue Proteins
Neurons
RNA, Long Noncoding
RNA, Messenger
Retina
Signal Transduction
Spinocerebellar Ataxias
Transcription Initiation, Genetic

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10.1038/nsmb.2902

Keith Vance
- K.W.Vancebath.acuk
- Department of Life Sciences - Senior Lecturer
Person: Research & Teaching

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Tan, J. Y., Vance, K. W., Varela, M. A., Sirey, T., Watson, L. M., Curtis, H. J., Marinello, M., Alves, S., Steinkraus, B. R., Cooper, S., Nesterova, T., Brockdorff, N., Fulga, T. A., Brice, A., Sittler, A., Oliver, P. L., Wood, M. J., Ponting, C. P., & Marques, A. C. (2014). Cross-talking noncoding RNAs contribute to cell-specific neurodegeneration in SCA7. Nature Structural and Molecular Biology, 21(11), 955-961. https://doi.org/10.1038/nsmb.2902

Tan, JY, Vance, KW, Varela, MA, Sirey, T, Watson, LM, Curtis, HJ, Marinello, M, Alves, S, Steinkraus, BR, Cooper, S, Nesterova, T, Brockdorff, N, Fulga, TA, Brice, A, Sittler, A, Oliver, PL, Wood, MJ, Ponting, CP & Marques, AC 2014, 'Cross-talking noncoding RNAs contribute to cell-specific neurodegeneration in SCA7', Nature Structural and Molecular Biology, vol. 21, no. 11, pp. 955-961. https://doi.org/10.1038/nsmb.2902

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abstract = "What causes the tissue-specific pathology of diseases resulting from mutations in housekeeping genes? Specifically, in spinocerebellar ataxia type 7 (SCA7), a neurodegenerative disorder caused by a CAG-repeat expansion in ATXN7 (which encodes an essential component of the mammalian transcription coactivation complex, STAGA), the factors underlying the characteristic progressive cerebellar and retinal degeneration in patients were unknown. We found that STAGA is required for the transcription initiation of miR-124, which in turn mediates the post-transcriptional cross-talk between lnc-SCA7, a conserved long noncoding RNA, and ATXN7 mRNA. In SCA7, mutations in ATXN7 disrupt these regulatory interactions and result in a neuron-specific increase in ATXN7 expression. Strikingly, in mice this increase is most prominent in the SCA7 disease-relevant tissues, namely the retina and cerebellum. Our results illustrate how noncoding RNA-mediated feedback regulation of a ubiquitously expressed housekeeping gene may contribute to specific neurodegeneration.",

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AU - Curtis, Helen J

AU - Marinello, Martina

AU - Alves, Sandro

AU - Steinkraus, Bruno R

AU - Cooper, Sarah

AU - Nesterova, Tatyana

AU - Brockdorff, Neil

AU - Fulga, Tudor A

AU - Brice, Alexis

AU - Sittler, Annie

AU - Oliver, Peter L

AU - Wood, Matthew J

AU - Ponting, Chris P

AU - Marques, Ana C

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KW - Gene Expression Regulation

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KW - Male

KW - Mice

KW - MicroRNAs

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ER -

Cross-talking noncoding RNAs contribute to cell-specific neurodegeneration in SCA7

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Keywords

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Keith Vance

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