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

TY - JOUR

T1 - 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

AU - Muñoz-Cobo, Juan Pablo

AU - Sánchez-Hernández, Noemí

AU - Gutiérrez-Enríquez, Sara

AU - El Yousfi, Younes

AU - Montes, Marta

AU - Gallego, Carme

AU - Hernández-Munain, Cristina

AU - Suñé, Carlos

PY - 2017/12/1

Y1 - 2017/12/1

N2 - 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.

AB - 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.

KW - Alternative splicing

KW - Cytoskeleton

KW - Dendrites

KW - Neurite outgrowth

KW - TCERG1

KW - Transcription

U2 - 10.1007/s12035-016-0284-6

DO - 10.1007/s12035-016-0284-6

M3 - Journal article

C2 - 27844289

AN - SCOPUS:84995451755

SN - 0893-7648

SP - 1

EP - 16

JO - Molecular Neurobiology

JF - Molecular Neurobiology

M1 - s12035-016-0284-6

ER -