Disease-associated astrocyte epigenetic memory promotes CNS pathology
This article has been Reviewed by the following groups
Listed in
- Evaluated articles (Arcadia Science)
Abstract
Astrocytes play important roles in the central nervous system (CNS) physiology and pathology. Indeed, astrocyte subsets defined by specific transcriptional activation states contribute to the pathology of neurologic diseases, including multiple sclerosis (MS) and its pre-clinical model experimental autoimmune encephalomyelitis (EAE) 1–8 . However, little is known about the stability of these disease-associated astrocyte subsets, their regulation, and whether they integrate past stimulation events to respond to subsequent challenges. Here, we describe the identification of an epigenetically controlled memory astrocyte subset which exhibits exacerbated pro-inflammatory responses upon re-challenge. Specifically, using a combination of single-cell RNA sequencing (scRNA-seq), assay for transposase-accessible chromatin with sequencing (ATAC–seq), chromatin immunoprecipitation with sequencing (ChIP–seq), focused interrogation of cells by nucleic acid detection and sequencing (FIND-seq), and cell-specific in vivo CRISPR/Cas9-based genetic perturbation studies we established that astrocyte memory is controlled by the metabolic enzyme ATP citrate lyase (ACLY), which produces acetyl coenzyme A (acetyl-CoA) used by the histone acetyltransferase p300 to control chromatin accessibility. ACLY + p300 + memory astrocytes are increased in acute and chronic EAE models; the genetic targeting of ACLY + p300 + astrocytes using CRISPR/Cas9 ameliorated EAE. We also detected responses consistent with a pro-inflammatory memory phenotype in human astrocytes in vitro ; scRNA-seq and immunohistochemistry studies detected increased ACLY + p300 + astrocytes in chronic MS lesions. In summary, these studies define an epigenetically controlled memory astrocyte subset that promotes CNS pathology in EAE and, potentially, MS. These findings may guide novel therapeutic approaches for MS and other neurologic diseases.
Article activity feed
-
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.
-
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?
-
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?
-
