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Transcriptional Elongation Regulator 1 Affects Transcription and Splicing of Genes Associated with Cellular Morphology and Cytoskeleton Dynamics and Is Required for Neurite Outgrowth in Neuroblastoma Cells and Primary Neuronal Cultures

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Abstract

TCERG1 is a highly conserved human protein implicated in interactions with the transcriptional and splicing machinery that is associated with neurodegenerative disorders. Biochemical, neuropathological, and genetic evidence suggests an important role for TCERG1 in Huntington’s disease (HD) pathogenesis. At present, the molecular mechanism underlying TCERG1-mediated neuronal effects is unknown. Here, we show that TCERG1 depletion led to widespread alterations in mRNA processing that affected different types of alternative transcriptional or splicing events, indicating that TCERG1 plays a broad role in the regulation of alternative splicing. We observed considerable changes in the transcription and alternative splicing patterns of genes involved in cytoskeleton dynamics and neurite outgrowth. Accordingly, TCERG1 depletion in the neuroblastoma SH-SY5Y cell line and primary mouse neurons affected morphogenesis and resulted in reduced dendritic outgrowth, with a major effect on dendrite ramification and branching complexity. These defects could be rescued by ectopic expression of TCERG1. Our results indicate that TCERG1 affects expression of multiple mRNAs involved in neuron projection development, whose misregulation may be involved in TCERG1-linked neurological disorders.

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Abbreviations

TCERG1:

Transcription elongation regulator 1

HD:

Huntington’s disease

RNAPII:

RNA polymerase II;

qPCR:

Quantitative PCR

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Acknowledgements

We are grateful to many colleagues for their helpful suggestions, critical discussions, and comments. The technical assistance of Laura Montosa and Eduardo Andrés-León during the confocal microscopy and bioinformatic studies is gratefully acknowledged.

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Author notes

  1. Noemí Sánchez-Hernández

    Present address: Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, SE-106 91, Stockholm, Sweden

  2. Marta Montes

    Present address: Biotech Research and Innovation Centre, University of Copenhagen, Ole Maaløes Vej 5, DK-2200, Copenhagen, Denmark

Authors and Affiliations

  1. Department of Molecular Biology, Institute of Parasitology and Biomedicine “López Neyra” (IPBLN-CSIC), PTS, 18016, Granada, Spain

    Juan Pablo Muñoz-Cobo, Noemí Sánchez-Hernández, Younes El Yousfi, Marta Montes & Carlos Suñé

  2. Molecular Biology Institute of Barcelona (IBMB-CSIC), 08028, Barcelona, Spain

    Sara Gutiérrez & Carme Gallego

  3. Department of Cell Biology and Immunology, Institute of Parasitology and Biomedicine “López Neyra” (IPBLN-CSIC), PTS, 18016, Granada, Spain

    Cristina Hernández-Munain

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  1. Juan Pablo Muñoz-Cobo
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Correspondence to Carlos Suñé.

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Funding

This work was supported by grants from the Spanish Ministry of Economy and Competitiveness (grant number BFU2014–54660-R) and the Andalusian Government (Excellence Project BIO-2515/2012) to C.S. and from the Spanish Ministry of Economy and Competitiveness (grant number BFU2013–44660-R) and the Andalusian Government (Excellence Project CTS-6587) to C.H.M. Support from the European Region Development Fund (ERDF [FEDER]), is also acknowledged.

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Muñoz-Cobo, J.P., Sánchez-Hernández, N., Gutiérrez, S. et al. Transcriptional Elongation Regulator 1 Affects Transcription and Splicing of Genes Associated with Cellular Morphology and Cytoskeleton Dynamics and Is Required for Neurite Outgrowth in Neuroblastoma Cells and Primary Neuronal Cultures. Mol Neurobiol 54, 7808–7823 (2017). https://doi.org/10.1007/s12035-016-0284-6

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