Disease-associated astrocyte epigenetic memory promotes CNS pathology
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Abstract
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This increased activation of NF-kB-driven transcriptional modules may reflect both the increased accessibility of NF-kB to DNAresponsive elements as well as the heightened recruitment of NF-kB via protein-protein interactions,boosting pathogenic activities in memory astrocytes
Given the potential role of glucocorticoid receptors in antagonizing NF-kB signaling, is there any evidence of discrete or cryptic GR response elements in the promoters of NF-kB-driven transcriptional modules? I'm curious if different GR agonists could reverse promoter-specific p300-dependent acetylation and the associated neurodegenerative phenotypes.
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Ep300 inactivation in CNS astrocytes ameliorated EAE, reduceddemyelination, and suppressed pro-inflammatory astrocyte responses as determined by RNA-seqbut did not affect CNS-recruited or peripheral CD4+ T cells
Are there other attributes of astrocyte health that could be assessed to examine if p300 downregulation is not having detrimental effects?
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Indeed, we also identified Ep300, which encodes histone acetyltransferase (HAT)p300, as an upstream regulator of the transcriptional response of astrocytes to 2X IL-1β+TNFstimulation
This is a beautiful study showing that epigenic memory in astrocytes can prime cells towards CNS pathologies. From examination of unregulated genes and DNA binding sites in the promotor of p300 or ACLY, are there any candidate transcription factors that could be responsible for the upregulation by IL-1b and TNF?
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