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Series GSE68713 Query DataSets for GSE68713
Status Public on Apr 04, 2016
Title Propogation of anxiety-traits through the maternal line via parallel and segregated gametic and non-gametic epigenetic mechanisms
Organism Mus musculus
Experiment type Methylation profiling by high throughput sequencing
Expression profiling by high throughput sequencing
Summary Maternal stress, anxiety, and depression increase the risk of psychiatric disorders in the progeny. These maternal effects can extend beyond the first generation and affect the grandchildren. In contrast to paternal, maternal effects can impact the offspring not only during gametogenesis, but also through fetal and early-postnatal life, increasing phenotypic complexity and the overall impact. To better understand its non-genetic structure, we dissected a complex maternally-transmitted phenotype to elementary behaviors and their corresponding transmission mechanisms. Chronic stress and depression are associated with reduced serotonin1A receptor (5-HT1AR) levels, and we reported that 5-HT1AR+/- dams transmit anxiety/stress-reactivity traits to their wild-type offspring. Here we show that the maternal effect is propagated to multiple generations, and that the behavioral traits are not transmitted in unison, but rather via parallel and segregated mechanisms, each with generation-dependent penetrance and gender specificity. The “risk-avoidance” and “hypoactivity” traits of anxiety were transmitted, via a neuro-immune pathway, consecutively from mother to the wild-type F1, F2, and occasionally F3 generation by iterative non-gametic-programming, while the “increased stress-reactivity” trait was transmitted to the F2 generation by gametic-programming. Iterative non-gametic-programming of anxiety was linked, via gene expression changes and clustered DNA hypo/hypermethylation at intragenic enhancers, to sphingolipid metabolism and GPCRs in the F1/F2 hippocampus, suggesting dysregulated lipid raft functioning/transmembrane signaling. Conversely, gametic-programming of behavior was predominantly associated with hypomethylation at different promoter-enhancing sequences within a set of genes with diverse neuronal functions. Since differential methylation appeared only postnatally in F2 neurons and was absent in F3 neurons, it is secondary to earlier F2 gametic changes that survive reprogramming in the early embryo, but are erased in F3 germ-cells. Our data introduce parallel and segregated non-genetic transmission of traits as a mechanism that may explain the propagation and pleiotropy of complex behavioral and psychiatric disease phenotypes across generations.
Overall design Compared three generations of male offspring from wild-type and 5HT1A-R-/+ Swiss Webster mothers with two replicates per sample. Included as well is F2 embryo transfer from wild-type and het parents in wild-type surogates
Contributor(s) Mitchell E, Klein SL, Sharma A, Toth JG, Argyropoulos K, Barboza L, Bavley C, Bortolozzi A, Artigas F, Oh J, Lodhi N, Dudakov J, Toth M
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Submission date May 11, 2015
Last update date May 15, 2019
Contact name Shifra Liba Klein
Organization name Weill Cornell
Department Pharmacology
Lab Toth
Street address 1300 York Avenue
City New York
State/province NY
ZIP/Postal code 10065
Country USA
Platforms (1)
GPL13112 Illumina HiSeq 2000 (Mus musculus)
Samples (18)
GSM1679432 vDG_WT_1 (eRRBS)
GSM1679433 vDG_WT_2 (eRRBS)
GSM1679434 vDG_F1_1 (eRRBS)
BioProject PRJNA283490
SRA SRP058175

Download family Format
SOFT formatted family file(s) SOFTHelp
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Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE68713_RAW.tar 266.7 Mb (http)(custom) TAR (of TXT, WIG)
SRA Run SelectorHelp
Raw data are available in SRA
Processed data provided as supplementary file

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