An integrated systems analysis implicates EGR1 downregulation in simian immunodeficiency virus encephalitis-induced neural dysfunction

Merril Gersten, Mehrdad Alirezaei, Maria Cecilia Garibaldi Marcondes, Claudia Flynn, Timothy Ravasi, Trey Ideker, Howard S Fox

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

Human immunodeficiency virus (HIV)-associated dementia (HAD) is a syndrome occurring in HIV-infected patients with advanced disease that likely develops as a result of macrophage and microglial activation as well as other immune events triggered by virus in the central nervous system. The most relevant experimental model of HAD, rhesus macaques exhibiting simian immunodeficiency virus (SIV) encephalitis (SIVE), closely reproduces the human disease and has been successfully used to advance our understanding of mechanisms underlying HAD. In this study we integrate gene expression data from uninfected and SIV-infected hippocampus with a human protein interaction network and discover modules of genes whose expression patterns distinguish these two states, to facilitate identification of neuronal genes that may contribute to SIVE/HIV cognitive deficits. Using this approach we identify several downregulated candidate genes and select one, EGR1, a key molecule in hippocampus-related learning and memory, for further study. We show that EGR1 is downregulated in SIV-infected hippocampus and that it can be downregulated in differentiated human neuroblastoma cells by treatment with CCL8, a product of activated microglia. Integration of expression data with protein interaction data to discover discriminatory modules of interacting proteins can be usefully used to prioritize differentially expressed genes for further study. Investigation of EGR1, selected in this manner, indicates that its downregulation in SIVE may occur as a consequence of the host response to infection, leading to deficits in cognition.

Original languageEnglish (US)
Pages (from-to)12467-12476
Number of pages10
JournalJournal of Neuroscience
Volume29
Issue number40
DOIs
StatePublished - Oct 7 2009

Fingerprint

Simian Immunodeficiency Virus
Encephalitis
Systems Analysis
Down-Regulation
AIDS Dementia Complex
Hippocampus
HIV
Genes
Protein Interaction Maps
Gene Expression
Macrophage Activation
Microglia
Macaca mulatta
Neuroblastoma
Cognition
Dementia
Proteins
Theoretical Models
Central Nervous System
Learning

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

An integrated systems analysis implicates EGR1 downregulation in simian immunodeficiency virus encephalitis-induced neural dysfunction. / Gersten, Merril; Alirezaei, Mehrdad; Marcondes, Maria Cecilia Garibaldi; Flynn, Claudia; Ravasi, Timothy; Ideker, Trey; Fox, Howard S.

In: Journal of Neuroscience, Vol. 29, No. 40, 07.10.2009, p. 12467-12476.

Research output: Contribution to journalArticle

Gersten, Merril ; Alirezaei, Mehrdad ; Marcondes, Maria Cecilia Garibaldi ; Flynn, Claudia ; Ravasi, Timothy ; Ideker, Trey ; Fox, Howard S. / An integrated systems analysis implicates EGR1 downregulation in simian immunodeficiency virus encephalitis-induced neural dysfunction. In: Journal of Neuroscience. 2009 ; Vol. 29, No. 40. pp. 12467-12476.
@article{307482126ab04d2bb372518d8e861d86,
title = "An integrated systems analysis implicates EGR1 downregulation in simian immunodeficiency virus encephalitis-induced neural dysfunction",
abstract = "Human immunodeficiency virus (HIV)-associated dementia (HAD) is a syndrome occurring in HIV-infected patients with advanced disease that likely develops as a result of macrophage and microglial activation as well as other immune events triggered by virus in the central nervous system. The most relevant experimental model of HAD, rhesus macaques exhibiting simian immunodeficiency virus (SIV) encephalitis (SIVE), closely reproduces the human disease and has been successfully used to advance our understanding of mechanisms underlying HAD. In this study we integrate gene expression data from uninfected and SIV-infected hippocampus with a human protein interaction network and discover modules of genes whose expression patterns distinguish these two states, to facilitate identification of neuronal genes that may contribute to SIVE/HIV cognitive deficits. Using this approach we identify several downregulated candidate genes and select one, EGR1, a key molecule in hippocampus-related learning and memory, for further study. We show that EGR1 is downregulated in SIV-infected hippocampus and that it can be downregulated in differentiated human neuroblastoma cells by treatment with CCL8, a product of activated microglia. Integration of expression data with protein interaction data to discover discriminatory modules of interacting proteins can be usefully used to prioritize differentially expressed genes for further study. Investigation of EGR1, selected in this manner, indicates that its downregulation in SIVE may occur as a consequence of the host response to infection, leading to deficits in cognition.",
author = "Merril Gersten and Mehrdad Alirezaei and Marcondes, {Maria Cecilia Garibaldi} and Claudia Flynn and Timothy Ravasi and Trey Ideker and Fox, {Howard S}",
year = "2009",
month = "10",
day = "7",
doi = "10.1523/JNEUROSCI.3180-09.2009",
language = "English (US)",
volume = "29",
pages = "12467--12476",
journal = "Journal of Neuroscience",
issn = "0270-6474",
publisher = "Society for Neuroscience",
number = "40",

}

TY - JOUR

T1 - An integrated systems analysis implicates EGR1 downregulation in simian immunodeficiency virus encephalitis-induced neural dysfunction

AU - Gersten, Merril

AU - Alirezaei, Mehrdad

AU - Marcondes, Maria Cecilia Garibaldi

AU - Flynn, Claudia

AU - Ravasi, Timothy

AU - Ideker, Trey

AU - Fox, Howard S

PY - 2009/10/7

Y1 - 2009/10/7

N2 - Human immunodeficiency virus (HIV)-associated dementia (HAD) is a syndrome occurring in HIV-infected patients with advanced disease that likely develops as a result of macrophage and microglial activation as well as other immune events triggered by virus in the central nervous system. The most relevant experimental model of HAD, rhesus macaques exhibiting simian immunodeficiency virus (SIV) encephalitis (SIVE), closely reproduces the human disease and has been successfully used to advance our understanding of mechanisms underlying HAD. In this study we integrate gene expression data from uninfected and SIV-infected hippocampus with a human protein interaction network and discover modules of genes whose expression patterns distinguish these two states, to facilitate identification of neuronal genes that may contribute to SIVE/HIV cognitive deficits. Using this approach we identify several downregulated candidate genes and select one, EGR1, a key molecule in hippocampus-related learning and memory, for further study. We show that EGR1 is downregulated in SIV-infected hippocampus and that it can be downregulated in differentiated human neuroblastoma cells by treatment with CCL8, a product of activated microglia. Integration of expression data with protein interaction data to discover discriminatory modules of interacting proteins can be usefully used to prioritize differentially expressed genes for further study. Investigation of EGR1, selected in this manner, indicates that its downregulation in SIVE may occur as a consequence of the host response to infection, leading to deficits in cognition.

AB - Human immunodeficiency virus (HIV)-associated dementia (HAD) is a syndrome occurring in HIV-infected patients with advanced disease that likely develops as a result of macrophage and microglial activation as well as other immune events triggered by virus in the central nervous system. The most relevant experimental model of HAD, rhesus macaques exhibiting simian immunodeficiency virus (SIV) encephalitis (SIVE), closely reproduces the human disease and has been successfully used to advance our understanding of mechanisms underlying HAD. In this study we integrate gene expression data from uninfected and SIV-infected hippocampus with a human protein interaction network and discover modules of genes whose expression patterns distinguish these two states, to facilitate identification of neuronal genes that may contribute to SIVE/HIV cognitive deficits. Using this approach we identify several downregulated candidate genes and select one, EGR1, a key molecule in hippocampus-related learning and memory, for further study. We show that EGR1 is downregulated in SIV-infected hippocampus and that it can be downregulated in differentiated human neuroblastoma cells by treatment with CCL8, a product of activated microglia. Integration of expression data with protein interaction data to discover discriminatory modules of interacting proteins can be usefully used to prioritize differentially expressed genes for further study. Investigation of EGR1, selected in this manner, indicates that its downregulation in SIVE may occur as a consequence of the host response to infection, leading to deficits in cognition.

UR - http://www.scopus.com/inward/record.url?scp=70349883847&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=70349883847&partnerID=8YFLogxK

U2 - 10.1523/JNEUROSCI.3180-09.2009

DO - 10.1523/JNEUROSCI.3180-09.2009

M3 - Article

C2 - 19812322

AN - SCOPUS:70349883847

VL - 29

SP - 12467

EP - 12476

JO - Journal of Neuroscience

JF - Journal of Neuroscience

SN - 0270-6474

IS - 40

ER -