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A systems approach identifies networks and genes linking sleep and stress: implications for neuropathology

ABSTRACT: Sleep dysfunction and stress susceptibility are co-morbid complex traits, which often precede and predispose patients to a variety of neuropsychiatric diseases. Here, we demonstrate multi-level organizations of genetic landscape, candidate genes, and molecular networks associated with 328 stress and sleep traits in a chronically stressed population of 338 (C57BL/6J×A/J) F2 mice. We constructed striatal gene co-expression networks, revealing functionally and cell-type-specific gene co-regulations important for stress and sleep. Using a composite ranking system, we identified network modules most relevant for 15 independent phenotypic categories, highlighting a mitochondria/synaptic module that links sleep and stress. The key network regulators of this module are overrepresented with genes implicated in neuropsychiatric diseases. Our work suggests the interplay between sleep, stress, and neuropathology emerge from genetic influences on gene expression and their collective organization through complex molecular networks, providing a framework to interrogate the mechanisms underlying sleep, stress susceptibility, and related neuropathology. Examination of genomic and transcriptomic networks in a random subset of 100 (B6xA/J)F2 mice modeling the natural spectrum of stress susceptibility.

ORGANISM(S): Mus musculus

SUBMITTER: Bojan Losic

PROVIDER: E-GEOD-60312 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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A systems approach identifies networks and genes linking sleep and stress: implications for neuropathology

Project description:Sleep dysfunction and stress susceptibility are co-morbid complex traits, which often precede and predispose patients to a variety of neuropsychiatric diseases. Here, we demonstrate multi-level organizations of genetic landscape, candidate genes, and molecular networks associated with 328 stress and sleep traits in a chronically stressed population of 338 (C57BL/6J×A/J) F2 mice. We constructed striatal gene co-expression networks, revealing functionally and cell-type-specific gene co-regulations important for stress and sleep. Using a composite ranking system, we identified network modules most relevant for 15 independent phenotypic categories, highlighting a mitochondria/synaptic module that links sleep and stress. The key network regulators of this module are overrepresented with genes implicated in neuropsychiatric diseases. Our work suggests the interplay between sleep, stress, and neuropathology emerge from genetic influences on gene expression and their collective organization through complex molecular networks, providing a framework to interrogate the mechanisms underlying sleep, stress susceptibility, and related neuropathology.

2015-01-08 | GSE60312 | GEO

Signaling to Transcription Networks in the Neuronal Retrograde Injury Response

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Genome-wide DNA methylation levels and altered cortisol stress reactivity following childhood trauma in humans

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2016-03-16 | E-GEOD-77445 | biostudies-arrayexpress

Expression data from HDFA cells exposed to nanosecond duration electrical pulses

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Expression data from U-937 cells exposed to nanosecond duration electrical pulses

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2016-02-16 | E-GEOD-77908 | biostudies-arrayexpress

Expression data from Jurkat Clone E-6 cells exposed to nanosecond duration electrical pulses

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2016-02-16 | E-GEOD-77907 | biostudies-arrayexpress

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2013-08-20 | E-GEOD-45152 | biostudies-arrayexpress

The exonuclease TREX1 constitutes an innate immune checkpoint limiting cGAS/STING-mediated anti- tumor immunity

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2024-03-12 | E-MTAB-13823 | biostudies-arrayexpress

PhoP regulon in pathogenic Escherichia coli

Project description:PhoP is considered a regulator of virulence despite being conserved in both pathogenic and non-pathogenic Enterobacteriaceae. While Escherichia coli strains represent both non-pathogenic commensal isolates and numerous virulent pathotypes, the PhoP virulence regulator has only been studied in commensal E. coli. To better understand how conserved transcription factors contribute to virulence, we characterized PhoP in pathogenic E. coli. Loss of phoP significantly attenuated E. coli during extraintestinal infection. This was not surprising since we demonstrated that PhoP differentially regulated the transcription of >600 genes. In addition to survival at acidic pH and resistance to polymyxin B, PhoP was required for repression of motility and oxygen-independent changes in the expression of primary dehydrogenase and terminal reductase respiratory chain components. All phenotypes have in common a reliance on an energized membrane. Thus, we hypothesized that PhoP mediated these effects by regulating genes that generate a proton motive force. Indeed, bacteria lacking PhoP exhibited a hyper-polarized membrane, and dissipation of the transmembrane electrochemical gradient increased the susceptibility of the phoP mutant to acidic pH, while inhibiting respiratory generation of the proton gradient restored resistance to antimicrobial peptides independent of lipopolysaccharide modification. These findings demonstrate a connection between PhoP, virulence, and the energized state of the membrane. Comparison of gene expression between wild-type CFT073 and a CFT073 phoP deletion mutant during logarithmic phase growth in LB medium. Three biological replicates were compared from each strain.

2011-07-28 | E-GEOD-31029 | biostudies-arrayexpress

Epigenomic profiling in visceral white adipose tissue of offspring of mice exposed to late gestational sleep fragmentation

Project description:Background: Late gestational sleep fragmentation (LG-SF) is one of the major perturbations associated with sleep apnea and other sleep disorders during pregnancy. Objectives: To investigate the effects of late LG-SF on the epigenome of visceral white adipose tissue (VWAT) in the offspring. Methods: Time-pregnant mice were exposed to LG-SF or control sleep (LG-SC) conditions during the last 6 days of gestation. We performed large-scale DNA methylation analyses using MeDIP coupled to microarrays (MeDIP-chip) in VWAT of 24-week-old LG-SF and LG-SC offspring (n=8 mice/group). Univariate multiple-testing adjusted statistical analyses were applied to identify differentially methylated regions (DMRs) between the groups. DMRs were mapped to their corresponding genes, and tested for potential overlaps with biological pathways and gene networks. Results: We detected 2148 DMRs between LG-SF and LG-SC groups (p< 0.0001, MAT algorithm). A large proportion of the DMR-associated genes have reported functions that are altered in obesity and metabolic syndrome. Overrepresented pathways and gene networks were related to metabolic regulation and inflammatory response. Conclusions: Our findings show a major role for epigenomic regulation of pathways associated to metabolic processes and inflammatory response in VWAT. Furthermore, LG-SF-induced epigenetic alterations appear to increase the susceptibility to obesity and metabolic syndrome in the offspring. 16 mouse VWAT samples were analyzed by MeDIP coupled to microarray analysis: Offspring of mothers exposed to late-gestational sleep fragmentation (n=8, LG-SF group) and offspring of mothers mouse exposed to normal sleep conditions (n=8, LG-SC group)

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