Parkinson's disease genetic risk in a midbrain neuronal cell line
In genome-wide association studies of complex diseases, many risk polymorphisms are found to lie in non-coding DNA and likely confer risk through allele-dependent differences in gene regulatory elements. However, because distal regulatory elements can alter gene expression at various distances on li...
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doaj-6a2cfec1199e409b94f45885fbc4ba2d2021-03-22T12:46:17ZengElsevierNeurobiology of Disease1095-953X2018-06-011145364Parkinson's disease genetic risk in a midbrain neuronal cell lineSteven E. Pierce0Trevor Tyson1Alix Booms2Jordan Prahl3Gerhard A. Coetzee4Center for Neurodegenerative Science, Van Andel Research Institute, Grand Rapids, MI, United StatesCenter for Neurodegenerative Science, Van Andel Research Institute, Grand Rapids, MI, United StatesCenter for Neurodegenerative Science, Van Andel Research Institute, Grand Rapids, MI, United StatesCenter for Neurodegenerative Science, Van Andel Research Institute, Grand Rapids, MI, United StatesCorresponding author at: Van Andel Research Institute, 333 Bostwick Ave., N.E., Grand Rapids, MI 49503, United States.; Center for Neurodegenerative Science, Van Andel Research Institute, Grand Rapids, MI, United StatesIn genome-wide association studies of complex diseases, many risk polymorphisms are found to lie in non-coding DNA and likely confer risk through allele-dependent differences in gene regulatory elements. However, because distal regulatory elements can alter gene expression at various distances on linear DNA, the identity of relevant genes is unknown for most risk loci. In Parkinson's disease, at least some genetic risk is likely intrinsic to a neuronal subpopulation of cells in the brain regions affected. In order to compare neuron-relevant methods of pairing risk polymorphisms to target genes as well as to further characterize a single-cell model of a neurodegenerative disease, we used the portionally-dopaminergic, neuronal, mesencephalic-derived cell line LUHMES to dissect differentiation-specific mechanisms of gene expression. We compared genome-wide gene expression in undifferentiated and differentiated cells with genome-wide histone H3K27ac and CTCF-bound regions. Whereas promoters and CTCF binding were largely consistent between differentiated and undifferentiated cells, enhancers were mostly unique. We matched the differentiation-specific appearance or disappearance of enhancers with changes in gene expression and identified 22,057 enhancers paired with 6388 differentially expressed genes by proximity. These enhancers are enriched with at least 13 transcription factor response elements, driving a cluster of genes involved in neurogenesis. We show that differentiated LUHMES cells, but not undifferentiated cells, show enrichment for PD-risk SNPs. Candidate genes for these loci are largely unrelated, though a subset is linked to synaptic vesicle cycling and transport, implying that PD-related disruption of these pathways is intrinsic to dopaminergic neurons.http://www.sciencedirect.com/science/article/pii/S0969996118300391Parkinson's diseaseLUHMESGenetic enhancersVesicle transportNeurogenesisDifferentiation |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Steven E. Pierce Trevor Tyson Alix Booms Jordan Prahl Gerhard A. Coetzee |
spellingShingle |
Steven E. Pierce Trevor Tyson Alix Booms Jordan Prahl Gerhard A. Coetzee Parkinson's disease genetic risk in a midbrain neuronal cell line Neurobiology of Disease Parkinson's disease LUHMES Genetic enhancers Vesicle transport Neurogenesis Differentiation |
author_facet |
Steven E. Pierce Trevor Tyson Alix Booms Jordan Prahl Gerhard A. Coetzee |
author_sort |
Steven E. Pierce |
title |
Parkinson's disease genetic risk in a midbrain neuronal cell line |
title_short |
Parkinson's disease genetic risk in a midbrain neuronal cell line |
title_full |
Parkinson's disease genetic risk in a midbrain neuronal cell line |
title_fullStr |
Parkinson's disease genetic risk in a midbrain neuronal cell line |
title_full_unstemmed |
Parkinson's disease genetic risk in a midbrain neuronal cell line |
title_sort |
parkinson's disease genetic risk in a midbrain neuronal cell line |
publisher |
Elsevier |
series |
Neurobiology of Disease |
issn |
1095-953X |
publishDate |
2018-06-01 |
description |
In genome-wide association studies of complex diseases, many risk polymorphisms are found to lie in non-coding DNA and likely confer risk through allele-dependent differences in gene regulatory elements. However, because distal regulatory elements can alter gene expression at various distances on linear DNA, the identity of relevant genes is unknown for most risk loci. In Parkinson's disease, at least some genetic risk is likely intrinsic to a neuronal subpopulation of cells in the brain regions affected. In order to compare neuron-relevant methods of pairing risk polymorphisms to target genes as well as to further characterize a single-cell model of a neurodegenerative disease, we used the portionally-dopaminergic, neuronal, mesencephalic-derived cell line LUHMES to dissect differentiation-specific mechanisms of gene expression. We compared genome-wide gene expression in undifferentiated and differentiated cells with genome-wide histone H3K27ac and CTCF-bound regions. Whereas promoters and CTCF binding were largely consistent between differentiated and undifferentiated cells, enhancers were mostly unique. We matched the differentiation-specific appearance or disappearance of enhancers with changes in gene expression and identified 22,057 enhancers paired with 6388 differentially expressed genes by proximity. These enhancers are enriched with at least 13 transcription factor response elements, driving a cluster of genes involved in neurogenesis. We show that differentiated LUHMES cells, but not undifferentiated cells, show enrichment for PD-risk SNPs. Candidate genes for these loci are largely unrelated, though a subset is linked to synaptic vesicle cycling and transport, implying that PD-related disruption of these pathways is intrinsic to dopaminergic neurons. |
topic |
Parkinson's disease LUHMES Genetic enhancers Vesicle transport Neurogenesis Differentiation |
url |
http://www.sciencedirect.com/science/article/pii/S0969996118300391 |
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