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Autosomal dominant retinitis pigmentosa rhodopsin mutant Q344X drives specific alterations in chromatin complex gene transcription

PURPOSE: Epigenetic and transcriptional mechanisms have been shown to contribute to long-lasting functional changes in adult neurons. The purpose of this study was to identify any such modifications in diseased retinal tissues from a mouse model of rhodopsin mutation-associated autosomal dominant re...

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Autores principales: Bales, Katie L., Ianov, Lara, Kennedy, Andrew J., Sweatt, J. David, Gross, Alecia K.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Molecular Vision 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5815338/
https://www.ncbi.nlm.nih.gov/pubmed/29463953
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author Bales, Katie L.
Ianov, Lara
Kennedy, Andrew J.
Sweatt, J. David
Gross, Alecia K.
author_facet Bales, Katie L.
Ianov, Lara
Kennedy, Andrew J.
Sweatt, J. David
Gross, Alecia K.
author_sort Bales, Katie L.
collection PubMed
description PURPOSE: Epigenetic and transcriptional mechanisms have been shown to contribute to long-lasting functional changes in adult neurons. The purpose of this study was to identify any such modifications in diseased retinal tissues from a mouse model of rhodopsin mutation-associated autosomal dominant retinitis pigmentosa (ADRP), Q344X, relative to age-matched wild-type (WT) controls. METHODS: We performed RNA sequencing (RNA-seq) at poly(A) selected RNA to profile the transcriptional patterns in 3-week-old ADRP mouse model rhodopsin Q344X compared to WT controls. Differentially expressed genes were determined by DESeq2 using the Benjamini & Hochberg p value adjustment and an absolute log(2) fold change cutoff. Quantitative western blots were conducted to evaluate protein expression levels of histone H3 phosphorylated at serine 10 and histone H4. qRT-PCR was performed to validate the expression patterns of differentially expressed genes. RESULTS: We observed significant differential expression in 2151 genes in the retina of Q344X mice compared to WT controls, including downregulation in the potassium channel gene, Kcnv2, and differential expression of histone genes, including the H1 family histone member, H1foo; the H3 histone family 3B, H3f3b; and the histone deacetylase 9, Hdac9. Quantitative western blots revealed statistically significant decreased protein expression of both histone H3 phosphorylated at serine 10 and histone H4 in 3-week-old Q344X retinas. Furthermore, qRT-PCR performed on select differentially expressed genes based on our RNA-seq results revealed matched expression patterns of up or downregulation. CONCLUSIONS: These findings provide evidence that transcriptomic alterations occur in the ADRP mouse model rhodopsin Q344X retina and that these processes may contribute to the dysfunction and neurodegeneration seen in this animal model.
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spelling pubmed-58153382018-02-20 Autosomal dominant retinitis pigmentosa rhodopsin mutant Q344X drives specific alterations in chromatin complex gene transcription Bales, Katie L. Ianov, Lara Kennedy, Andrew J. Sweatt, J. David Gross, Alecia K. Mol Vis Research Article PURPOSE: Epigenetic and transcriptional mechanisms have been shown to contribute to long-lasting functional changes in adult neurons. The purpose of this study was to identify any such modifications in diseased retinal tissues from a mouse model of rhodopsin mutation-associated autosomal dominant retinitis pigmentosa (ADRP), Q344X, relative to age-matched wild-type (WT) controls. METHODS: We performed RNA sequencing (RNA-seq) at poly(A) selected RNA to profile the transcriptional patterns in 3-week-old ADRP mouse model rhodopsin Q344X compared to WT controls. Differentially expressed genes were determined by DESeq2 using the Benjamini & Hochberg p value adjustment and an absolute log(2) fold change cutoff. Quantitative western blots were conducted to evaluate protein expression levels of histone H3 phosphorylated at serine 10 and histone H4. qRT-PCR was performed to validate the expression patterns of differentially expressed genes. RESULTS: We observed significant differential expression in 2151 genes in the retina of Q344X mice compared to WT controls, including downregulation in the potassium channel gene, Kcnv2, and differential expression of histone genes, including the H1 family histone member, H1foo; the H3 histone family 3B, H3f3b; and the histone deacetylase 9, Hdac9. Quantitative western blots revealed statistically significant decreased protein expression of both histone H3 phosphorylated at serine 10 and histone H4 in 3-week-old Q344X retinas. Furthermore, qRT-PCR performed on select differentially expressed genes based on our RNA-seq results revealed matched expression patterns of up or downregulation. CONCLUSIONS: These findings provide evidence that transcriptomic alterations occur in the ADRP mouse model rhodopsin Q344X retina and that these processes may contribute to the dysfunction and neurodegeneration seen in this animal model. Molecular Vision 2018-02-15 /pmc/articles/PMC5815338/ /pubmed/29463953 Text en Copyright © 2018 Molecular Vision. http://creativecommons.org/licenses/by-nc-nd/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited, used for non-commercial purposes, and is not altered or transformed.
spellingShingle Research Article
Bales, Katie L.
Ianov, Lara
Kennedy, Andrew J.
Sweatt, J. David
Gross, Alecia K.
Autosomal dominant retinitis pigmentosa rhodopsin mutant Q344X drives specific alterations in chromatin complex gene transcription
title Autosomal dominant retinitis pigmentosa rhodopsin mutant Q344X drives specific alterations in chromatin complex gene transcription
title_full Autosomal dominant retinitis pigmentosa rhodopsin mutant Q344X drives specific alterations in chromatin complex gene transcription
title_fullStr Autosomal dominant retinitis pigmentosa rhodopsin mutant Q344X drives specific alterations in chromatin complex gene transcription
title_full_unstemmed Autosomal dominant retinitis pigmentosa rhodopsin mutant Q344X drives specific alterations in chromatin complex gene transcription
title_short Autosomal dominant retinitis pigmentosa rhodopsin mutant Q344X drives specific alterations in chromatin complex gene transcription
title_sort autosomal dominant retinitis pigmentosa rhodopsin mutant q344x drives specific alterations in chromatin complex gene transcription
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5815338/
https://www.ncbi.nlm.nih.gov/pubmed/29463953
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