Modest changes in Spi1 dosage reveal the potential for altered microglial function as seen in Alzheimer’s disease

Abstract Genetic association studies have identified multiple variants at the SPI1 locus that modify risk and age of onset for Alzheimer’s Disease (AD). Reports linking risk variants to gene expression suggest that variants denoting higher SPI1 expression are likely to have an earlier AD onset, and...

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Autores principales:	Ruth E. Jones, Robert Andrews, Peter Holmans, Matthew Hill, Philip R. Taylor
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/1fcd18bed3f04a0bb075f55614d05cce
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spelling	oai:doaj.org-article:1fcd18bed3f04a0bb075f55614d05cce2021-12-02T16:26:29ZModest changes in Spi1 dosage reveal the potential for altered microglial function as seen in Alzheimer’s disease10.1038/s41598-021-94324-z2045-2322https://doaj.org/article/1fcd18bed3f04a0bb075f55614d05cce2021-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-94324-zhttps://doaj.org/toc/2045-2322Abstract Genetic association studies have identified multiple variants at the SPI1 locus that modify risk and age of onset for Alzheimer’s Disease (AD). Reports linking risk variants to gene expression suggest that variants denoting higher SPI1 expression are likely to have an earlier AD onset, and several other AD risk genes contain PU.1 binding sites in the promoter region. Overall, this suggests the level of SPI1 may alter microglial phenotype potentially impacting AD. This study determined how the microglial transcriptome was altered following modest changes to Spi1 expression in primary mouse microglia. RNA-sequencing was performed on microglia with reduced or increased Spi1/PU.1 expression to provide an unbiased approach to determine transcriptomic changes affected by Spi1. In summary, a reduction in microglial Spi1 resulted in the dysregulation of transcripts encoding proteins involved in DNA replication pathways while an increased Spi1 results in an upregulation of genes associated with immune response pathways. Additionally, a subset of 194 Spi1 dose-sensitive genes was identified and pathway analysis suggests that several innate immune and interferon response pathways are impacted by the concentration of Spi1. Together these results suggest Spi1 levels can alter the microglial transcriptome and suggests interferon pathways may be altered in individuals with AD related Spi1 risk SNPs.Ruth E. JonesRobert AndrewsPeter HolmansMatthew HillPhilip R. TaylorNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-14 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Ruth E. Jones Robert Andrews Peter Holmans Matthew Hill Philip R. Taylor Modest changes in Spi1 dosage reveal the potential for altered microglial function as seen in Alzheimer’s disease
description	Abstract Genetic association studies have identified multiple variants at the SPI1 locus that modify risk and age of onset for Alzheimer’s Disease (AD). Reports linking risk variants to gene expression suggest that variants denoting higher SPI1 expression are likely to have an earlier AD onset, and several other AD risk genes contain PU.1 binding sites in the promoter region. Overall, this suggests the level of SPI1 may alter microglial phenotype potentially impacting AD. This study determined how the microglial transcriptome was altered following modest changes to Spi1 expression in primary mouse microglia. RNA-sequencing was performed on microglia with reduced or increased Spi1/PU.1 expression to provide an unbiased approach to determine transcriptomic changes affected by Spi1. In summary, a reduction in microglial Spi1 resulted in the dysregulation of transcripts encoding proteins involved in DNA replication pathways while an increased Spi1 results in an upregulation of genes associated with immune response pathways. Additionally, a subset of 194 Spi1 dose-sensitive genes was identified and pathway analysis suggests that several innate immune and interferon response pathways are impacted by the concentration of Spi1. Together these results suggest Spi1 levels can alter the microglial transcriptome and suggests interferon pathways may be altered in individuals with AD related Spi1 risk SNPs.
format	article
author	Ruth E. Jones Robert Andrews Peter Holmans Matthew Hill Philip R. Taylor
author_facet	Ruth E. Jones Robert Andrews Peter Holmans Matthew Hill Philip R. Taylor
author_sort	Ruth E. Jones
title	Modest changes in Spi1 dosage reveal the potential for altered microglial function as seen in Alzheimer’s disease
title_short	Modest changes in Spi1 dosage reveal the potential for altered microglial function as seen in Alzheimer’s disease
title_full	Modest changes in Spi1 dosage reveal the potential for altered microglial function as seen in Alzheimer’s disease
title_fullStr	Modest changes in Spi1 dosage reveal the potential for altered microglial function as seen in Alzheimer’s disease
title_full_unstemmed	Modest changes in Spi1 dosage reveal the potential for altered microglial function as seen in Alzheimer’s disease
title_sort	modest changes in spi1 dosage reveal the potential for altered microglial function as seen in alzheimer’s disease
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/1fcd18bed3f04a0bb075f55614d05cce
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Modest changes in Spi1 dosage reveal the potential for altered microglial function as seen in Alzheimer’s disease

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