Loss of the Spinocerebellar Ataxia type 3 disease protein ATXN3 alters transcription of multiple signal transduction pathways
| Autor: | Annie J. Zalon, Li Zeng, Henry L. Paulson, Dapeng Zhang, L. Aravind, Hayley S. McLoughlin |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
Male
0301 basic medicine Transcription Genetic Microarrays Gene Expression lcsh:Medicine Biochemistry Histones Gene Knockout Techniques Mice 0302 clinical medicine Cell Signaling Transcriptional regulation Ataxin-3 Promoter Regions Genetic lcsh:Science WNT Signaling Cascade Regulation of gene expression Multidisciplinary Transcriptional Control Wnt signaling pathway Acetylation Signaling Cascades Ephrin-A3 Cell biology Bioassays and Physiological Analysis Knockout mouse Spinocerebellar ataxia Female Signal transduction Signal Transduction Research Article Biology Research and Analysis Methods Histone Deacetylases Cell Line 03 medical and health sciences EPH receptor A3 Gene Types DNA-binding proteins Genetics medicine Animals Ephrin Gene Regulation lcsh:R Biology and Life Sciences Proteins Cell Biology medicine.disease 030104 developmental biology Gene Expression Regulation TGF-beta signaling cascade Regulator Genes lcsh:Q 030217 neurology & neurosurgery |
| Zdroj: | PLoS ONE, Vol 13, Iss 9, p e0204438 (2018) PLoS ONE |
| ISSN: | 1932-6203 |
| Popis: | Spinocerebellar ataxia type 3 (SCA3) is a dominantly inherited neurodegenerative disorder caused by a polyglutamine-encoding CAG repeat expansion in the ATXN3 gene which encodes the deubiquitinating enzyme, ATXN3. Several mechanisms have been proposed to explain the pathogenic role of mutant, polyQ-expanded ATXN3 in SCA3 including disease protein aggregation, impairment of ubiquitin-proteasomal degradation and transcriptional dysregulation. A better understanding of the normal functions of this protein may shed light on SCA3 disease pathogenesis. To assess the potential normal role of ATXN3 in regulating gene expression, we compared transcriptional profiles in WT versus Atxn3 null mouse embryonic fibroblasts. Differentially expressed genes in the absence of ATXN3 contribute to multiple signal transduction pathways, suggesting a status switch of signaling pathways including depressed Wnt and BMP4 pathways and elevated growth factor pathways such as Prolactin, TGF-β, and Ephrin pathways. The Eph receptor A3 (Efna3), a receptor protein-tyrosine kinase in the Ephrin pathway that is highly expressed in the nervous system, was the most differentially upregulated gene in Atxn3 null MEFs. This increased expression of Efna3 was recapitulated in Atxn3 knockout mouse brainstem, a selectively vulnerable brain region in SCA3. Overexpression of normal or expanded ATXN3 was sufficient to repress Efna3 expression, supporting a role for ATXN3 in regulating Ephrin signaling. We further show that, in the absence of ATXN3, Efna3 upregulation is associated with hyperacetylation of histones H3 and H4 at the Efna3 promoter, which in turn is induced by decreased levels of HDAC3 and NCoR in ATXN3 null cells. Together, these results reveal a normal role for ATXN3 in transcriptional regulation of multiple signaling pathways of potential relevance to disease processes in SCA3. |
| Databáze: | OpenAIRE |
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