Neuronal-specific microexon splicing of TAF1 mRNA is directly regulated by SRRM4/nSR100

Simona Capponi; Nadja Stöffler; Manuel Irimia; Frederik M.A. Van Schaik; Mercedes M. Ondik; Martin L. Biniossek; Lisa Lehmann; Julia Mitschke; Marit W. Vermunt; Menno P. Creyghton; Ann M. Graybiel; Thomas Reinheckel; Oliver Schilling; Benjamin J. Blencowe; Jill R. Crittenden; H. Th Marc Timmers

doi:10.1080/15476286.2019.1667214

Neuronal-specific microexon splicing of TAF1 mRNA is directly regulated by SRRM4/nSR100

Simona Capponi, Nadja Stöffler, Manuel Irimia, Frederik M.A. Van Schaik, Mercedes M. Ondik, Martin L. Biniossek, Lisa Lehmann, Julia Mitschke, Marit W. Vermunt, Menno P. Creyghton, Ann M. Graybiel, Thomas Reinheckel, Oliver Schilling, Benjamin J. Blencowe, Jill R. Crittenden, H. Th Marc Timmers^*

^*Corresponding author for this work

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Abstract

Neuronal microexons represent the most highly conserved class of alternative splicing events and their timed expression shapes neuronal biology, including neuronal commitment and differentiation. The six-nt microexon 34ʹ is included in the neuronal form of TAF1 mRNA, which encodes the largest subunit of the basal transcription factor TFIID. In this study, we investigate the tissue distribution of TAF1-34ʹ mRNA and protein and the mechanism responsible for its neuronal-specific splicing. Using isoform-specific RNA probes and antibodies, we observe that canonical TAF1 and TAF1-34ʹ have different distributions in the brain, which distinguish proliferating from post-mitotic neurons. Knockdown and ectopic expression experiments demonstrate that the neuronal-specific splicing factor SRRM4/nSR100 promotes the inclusion of microexon 34ʹ into TAF1 mRNA, through the recognition of UGC sequences in the poly-pyrimidine tract upstream of the regulated microexon. These results show that SRRM4 regulates temporal and spatial expression of alternative TAF1 mRNAs to generate a neuronal-specific TFIID complex.

Original language	English
Pages (from-to)	62-74
Number of pages	13
Journal	RNA biology
Volume	17
Issue number	1
DOIs	https://doi.org/10.1080/15476286.2019.1667214
Publication status	Published - 2 Jan 2020

Keywords

Alternative mRNA splicing
microexons
neuronal transcription
neurogenesis
basal transcription factors
TAF1
X-linked Dystonia Parkinsonism

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Neuronal specific microexon splicing of TAF1 mRNA is directly regulated by SRRM4 nSR100Final published version, 5.84 MB

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Capponi, S., Stöffler, N., Irimia, M., Van Schaik, F. M. A., Ondik, M. M., Biniossek, M. L., Lehmann, L., Mitschke, J., Vermunt, M. W., Creyghton, M. P., Graybiel, A. M., Reinheckel, T., Schilling, O., Blencowe, B. J., Crittenden, J. R., & Timmers, H. T. M. (2020). Neuronal-specific microexon splicing of TAF1 mRNA is directly regulated by SRRM4/nSR100. RNA biology, 17(1), 62-74. https://doi.org/10.1080/15476286.2019.1667214

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title = "Neuronal-specific microexon splicing of TAF1 mRNA is directly regulated by SRRM4/nSR100",

abstract = "Neuronal microexons represent the most highly conserved class of alternative splicing events and their timed expression shapes neuronal biology, including neuronal commitment and differentiation. The six-nt microexon 34ʹ is included in the neuronal form of TAF1 mRNA, which encodes the largest subunit of the basal transcription factor TFIID. In this study, we investigate the tissue distribution of TAF1-34ʹ mRNA and protein and the mechanism responsible for its neuronal-specific splicing. Using isoform-specific RNA probes and antibodies, we observe that canonical TAF1 and TAF1-34ʹ have different distributions in the brain, which distinguish proliferating from post-mitotic neurons. Knockdown and ectopic expression experiments demonstrate that the neuronal-specific splicing factor SRRM4/nSR100 promotes the inclusion of microexon 34ʹ into TAF1 mRNA, through the recognition of UGC sequences in the poly-pyrimidine tract upstream of the regulated microexon. These results show that SRRM4 regulates temporal and spatial expression of alternative TAF1 mRNAs to generate a neuronal-specific TFIID complex.",

keywords = "Alternative mRNA splicing, microexons, neuronal transcription, neurogenesis, basal transcription factors, TAF1, X-linked Dystonia Parkinsonism",

author = "Simona Capponi and Nadja St{\"o}ffler and Manuel Irimia and {Van Schaik}, {Frederik M.A.} and Ondik, {Mercedes M.} and Biniossek, {Martin L.} and Lisa Lehmann and Julia Mitschke and Vermunt, {Marit W.} and Creyghton, {Menno P.} and Graybiel, {Ann M.} and Thomas Reinheckel and Oliver Schilling and Blencowe, {Benjamin J.} and Crittenden, {Jill R.} and Timmers, {H. Th Marc}",

note = "Funding Information: We thank the present and past members of the Timmers laboratory for their support, discussions and critical reading of this manuscript. This work also benefitted from discussions with Dr. Paul Coffer and his group members (University Medical Center Utrecht, The Netherlands). We also thank Samitha Venu, Tomoko Yoshida, Marie Follo and Courtney Anderson, Emily Park, Mindy Wang, and Wei Wei from ACDBio for technical assistance. We thank Marcel Leist (University of Konstanz, Germany) for providing the LUHMES cells. This work was financially supported by the Collaborative Center for X-linked Dystonia Parkinsonism (CCXDP). We are particularly grateful for the stimulating discussions with all members of the CC-XDP and its inspirational leaders. Publisher Copyright: {\textcopyright} 2019, {\textcopyright} 2019 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. Copyright: Copyright 2020 Elsevier B.V., All rights reserved.",

year = "2020",

month = jan,

day = "2",

doi = "10.1080/15476286.2019.1667214",

language = "English",

volume = "17",

pages = "62--74",

number = "1",

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Capponi, S, Stöffler, N, Irimia, M, Van Schaik, FMA, Ondik, MM, Biniossek, ML, Lehmann, L, Mitschke, J, Vermunt, MW, Creyghton, MP, Graybiel, AM, Reinheckel, T, Schilling, O, Blencowe, BJ, Crittenden, JR & Timmers, HTM 2020, 'Neuronal-specific microexon splicing of TAF1 mRNA is directly regulated by SRRM4/nSR100', RNA biology, vol. 17, no. 1, pp. 62-74. https://doi.org/10.1080/15476286.2019.1667214

TY - JOUR

T1 - Neuronal-specific microexon splicing of TAF1 mRNA is directly regulated by SRRM4/nSR100

AU - Capponi, Simona

AU - Stöffler, Nadja

AU - Irimia, Manuel

AU - Van Schaik, Frederik M.A.

AU - Ondik, Mercedes M.

AU - Biniossek, Martin L.

AU - Lehmann, Lisa

AU - Mitschke, Julia

AU - Vermunt, Marit W.

AU - Creyghton, Menno P.

AU - Graybiel, Ann M.

AU - Reinheckel, Thomas

AU - Schilling, Oliver

AU - Blencowe, Benjamin J.

AU - Crittenden, Jill R.

AU - Timmers, H. Th Marc

N1 - Funding Information: We thank the present and past members of the Timmers laboratory for their support, discussions and critical reading of this manuscript. This work also benefitted from discussions with Dr. Paul Coffer and his group members (University Medical Center Utrecht, The Netherlands). We also thank Samitha Venu, Tomoko Yoshida, Marie Follo and Courtney Anderson, Emily Park, Mindy Wang, and Wei Wei from ACDBio for technical assistance. We thank Marcel Leist (University of Konstanz, Germany) for providing the LUHMES cells. This work was financially supported by the Collaborative Center for X-linked Dystonia Parkinsonism (CCXDP). We are particularly grateful for the stimulating discussions with all members of the CC-XDP and its inspirational leaders. Publisher Copyright: © 2019, © 2019 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. Copyright: Copyright 2020 Elsevier B.V., All rights reserved.

PY - 2020/1/2

Y1 - 2020/1/2

N2 - Neuronal microexons represent the most highly conserved class of alternative splicing events and their timed expression shapes neuronal biology, including neuronal commitment and differentiation. The six-nt microexon 34ʹ is included in the neuronal form of TAF1 mRNA, which encodes the largest subunit of the basal transcription factor TFIID. In this study, we investigate the tissue distribution of TAF1-34ʹ mRNA and protein and the mechanism responsible for its neuronal-specific splicing. Using isoform-specific RNA probes and antibodies, we observe that canonical TAF1 and TAF1-34ʹ have different distributions in the brain, which distinguish proliferating from post-mitotic neurons. Knockdown and ectopic expression experiments demonstrate that the neuronal-specific splicing factor SRRM4/nSR100 promotes the inclusion of microexon 34ʹ into TAF1 mRNA, through the recognition of UGC sequences in the poly-pyrimidine tract upstream of the regulated microexon. These results show that SRRM4 regulates temporal and spatial expression of alternative TAF1 mRNAs to generate a neuronal-specific TFIID complex.

AB - Neuronal microexons represent the most highly conserved class of alternative splicing events and their timed expression shapes neuronal biology, including neuronal commitment and differentiation. The six-nt microexon 34ʹ is included in the neuronal form of TAF1 mRNA, which encodes the largest subunit of the basal transcription factor TFIID. In this study, we investigate the tissue distribution of TAF1-34ʹ mRNA and protein and the mechanism responsible for its neuronal-specific splicing. Using isoform-specific RNA probes and antibodies, we observe that canonical TAF1 and TAF1-34ʹ have different distributions in the brain, which distinguish proliferating from post-mitotic neurons. Knockdown and ectopic expression experiments demonstrate that the neuronal-specific splicing factor SRRM4/nSR100 promotes the inclusion of microexon 34ʹ into TAF1 mRNA, through the recognition of UGC sequences in the poly-pyrimidine tract upstream of the regulated microexon. These results show that SRRM4 regulates temporal and spatial expression of alternative TAF1 mRNAs to generate a neuronal-specific TFIID complex.

KW - Alternative mRNA splicing

KW - microexons

KW - neuronal transcription

KW - neurogenesis

KW - basal transcription factors

KW - TAF1

KW - X-linked Dystonia Parkinsonism

UR - http://www.scopus.com/inward/record.url?scp=85073957949&partnerID=8YFLogxK

U2 - 10.1080/15476286.2019.1667214

DO - 10.1080/15476286.2019.1667214

M3 - Article

C2 - 31559909

AN - SCOPUS:85073957949

SN - 1547-6286

VL - 17

SP - 62

EP - 74

JO - RNA biology

JF - RNA biology

IS - 1

ER -

Neuronal-specific microexon splicing of TAF1 mRNA is directly regulated by SRRM4/nSR100

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