Transcriptomics,Multiomics

Dataset Information

3

Hippocampal expression data from FTY720- and vehicle-treated SCID mice following fear consolidation testing


ABSTRACT: FTY720/Fingolimod, an FDA-approved drug for treatment of multiple sclerosis, has beneficial effects in the CNS that are not yet well understood, independent of its effects on immune cell trafficking. Here we show that FTY720 enters the nucleus where it is phosphorylated by sphingosine kinase 2 (SphK2) and nuclear FTY720-P that accumulates there, binds and inhibits class I histone deacetylases (HDACs) enhancing specific histone acetylations. FTY720 is also phosphorylated in mice and accumulates in various brain regions, including hippocampus, inhibits HDACs and enhances histone acetylation and gene expression programs associated with memory and learning leading to improvement of memory impairment independently of its immunosuppressive actions. Our data suggest that sphingosine-1-phosphate and SphK2 play specific roles in memory functions and that FTY720 may be a useful adjuvant therapy to facilitate extinction of aversive memories. Microarrays were used to survey the effect of FTY720 treatment during contextual fear conditioning on hippocampal gene expression. Total RNA was isolated from individual hippocampi of SCID mice 1 hour following fear consolidation testing after the third day of FTY720 or saline treatment. Eight arrays were run in total: 4 FTY720-treated mice and 4 saline-treated control mice.

REANALYSIS of: E-GEOD-57015

ORGANISM(S): Mus musculus  

PROVIDER: E-GEOD-57015 | ExpressionAtlas | 2015-08-04

REPOSITORIES: ExpressionAtlas

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Publications

Active, phosphorylated fingolimod inhibits histone deacetylases and facilitates fear extinction memory.

Hait Nitai C NC   Wise Laura E LE   Allegood Jeremy C JC   O'Brien Megan M   Avni Dorit D   Reeves Thomas M TM   Knapp Pamela E PE   Lu Junyan J   Luo Cheng C   Miles Michael F MF   Milstien Sheldon S   Lichtman Aron H AH   Spiegel Sarah S  

Nature neuroscience 20140525 7


FTY720 (fingolimod), an FDA-approved drug for treatment of multiple sclerosis, has beneficial effects in the CNS that are not yet well understood, independent of its effects on immune cell trafficking. We show that FTY720 enters the nucleus, where it is phosphorylated by sphingosine kinase 2 (SphK2), and that nuclear FTY720-P binds and inhibits class I histone deacetylases (HDACs), enhancing specific histone acetylations. FTY720 is also phosphorylated in mice and accumulates in the brain, includ  ...[more]

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