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

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.

A Role for Pre-mRNA-PROCESSING PROTEIN 40C in the Control of Growth, Development, and Stress Tolerance in Arabidopsis thaliana

“…Proper control of gene expression and pre-mRNAs processing is crucial for eukaryotic organisms, and, indeed, many pre-mRNA processing events occur cotranscriptionally. PRP40 proteins appear to couple transcript elongation to the control of pre-mRNA splicing, but the global extent of their contribution to the regulation of gene expression networks, as well as their physiological roles, have only recently started to be characterized in higher eukaryotes (Munoz-Cobo et al, 2017). The founding member of this family (ScPRP40) was identified in yeast (Kao and Siliciano, 1996) and shown to be an essential splicing factor.…”

“…Saccharomyces cerevisiae PRP40 (ScPRP40) and its three human homologues, HsPRPF40A, HsPRPF40B, and HsTCERG1/CA150, have been extensively studied in the last two decades. While HsPRPF40A and HsPRPF40B were characterized as essential components of the early spliceosome assembly process (Lin et al, 2004; Wahl et al, 2009; Becerra et al, 2015), HsTCERG1/CA150 was initially discovered as a transcriptional modulator and later linked to pre-mRNA splicing (Sune et al, 1997; Pearson et al, 2008; Munoz-Cobo et al, 2017). In fact, HsTCERG1/CA150 has been found associated with elongation factors and is present in a complex with the RNA polymerase II via the FF domains (Sune et al, 1997; Carty et al, 2000; Sanchez-Alvarez et al, 2006).…”

Identification of novel non-myelin biomarkers in multiple sclerosis using an improved phage-display approach

“…Interestingly, both antigens that we have identified in this work are protein involved in the regulation of RNA processing and have been associated with neurodegenerative disorders. In particular, TCERG1 has a role in regulating alternative splicing of multiple RNA and its depletion reduces apoptotic processes [38] and leads to alterations in neurite outgrowth [39]. This correlates with the protective effect of TCERG1 overexpression against huntingtin toxicity promoting neuritic aggregates formation [40].…”

Identification of TCERG1 as a new genetic modulator of TDP-43 production in Drosophila

“…TCERG1 interacts with splicing factors [30, 43] and has been identified in highly purified spliceosomes in multiple studies [25, 43, 45, 50, 57]. TCERG1 can affect pre-mRNA splicing of several splicing reporters [43, 48, 53, 60], and of putative cellular targets identified by microarray analysis following TCERG1 knockdown [49, 53]. Based on these data, TCERG1 has been suggested to couple the transcribing RNAPII with spliceosome complexes to regulate co-transcriptional splicing events, a hypothesis that was supported by the demonstration that TCERG1 regulates the alternative splicing of the Bclx gene through the modulation the RNAPII transcription rate [48].…”

“…However, to date the molecular mechanisms underlying TCERG1-mediated neuronal effects remain largely unknown. A recent study showed that TCERG1 is required for normal neurite development in cultured cells, and suggested that abnormal regulation of the transcription and/or alternative splicing of TCERG1-specific targets may therefore play a role in the pathogenesis of TCERG1-associated neurological disorders [49].…”