Disease-associated astrocyte epigenetic memory promotes CNS pathology

Area of Science:

• Neuroscience
• Immunology
• Epigenetics

Background:

• Astrocytes are crucial in central nervous system (CNS) physiology and pathology.
• Disease-associated astrocyte subsets contribute to neurological disorders like multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE).
• The stability and regulation of these disease-associated astrocyte subsets, including their ability to form memory, remain largely unknown.

Approach:

• Utilized single-cell RNA sequencing (scRNA-seq), ATAC-seq, ChIP-seq, FIND-seq, and in vivo CRISPR/Cas9 genetic perturbations.
• Investigated the role of ATP citrate lyase (ACLY) and p300 in astrocyte memory formation and function.
• Examined astrocyte responses in both EAE models and human astrocytes in vitro.

Key Points:

• Identified an epigenetically controlled memory astrocyte subset exhibiting heightened pro-inflammatory responses upon re-challenge.
• Demonstrated that astrocyte memory is regulated by ACLY, which supplies acetyl-CoA to p300, controlling chromatin accessibility.
• Increased ACLY+p300+ memory astrocytes were observed in acute and chronic EAE models and in human MS lesions.
• Genetic targeting of ACLY+p300+ astrocytes via CRISPR/Cas9 significantly ameliorated EAE severity.

Conclusions:

• Defined a novel epigenetically regulated memory astrocyte subset that exacerbates CNS pathology in EAE and potentially MS.
• These findings highlight the role of ACLY and p300 in astrocyte memory and CNS inflammation.
• The study suggests potential therapeutic strategies targeting ACLY+p300+ astrocytes for MS and other neurological diseases.