Disease-associated astrocyte epigenetic memory promotes CNS pathology

Area of Science:

• Neuroscience
• Immunology
• Cell Biology

Background:

• Disease-associated astrocyte subsets are implicated in neurologic diseases such as multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE).
• The stability and memory of astrocyte responses to prior stimulation remain poorly understood.
• Understanding astrocyte behavior is crucial for developing effective treatments for CNS disorders.

Purpose of the Study:

• To identify and characterize stable, memory-prone astrocyte subsets involved in central nervous system (CNS) pathology.
• To elucidate the epigenetic mechanisms underlying astrocyte memory.
• To investigate the therapeutic potential of targeting these memory astrocytes in EAE and MS.

Main Methods:

• Single-cell RNA sequencing (scRNA-seq) and Assay for Transposase-Accessible Chromatin with Sequencing (ATAC-seq).
• Chromatin immunoprecipitation with sequencing (ChIP-seq) and CRISPR-Cas9 genetic perturbation.
• In vivo studies in EAE models and in vitro analysis of human astrocytes.

Main Results:

• Identification of an epigenetically regulated memory astrocyte subset characterized by ACLY+p300+ expression.
• Astrocyte memory is controlled by ATP-citrate lyase (ACLY) and histone acetyltransferase p300, regulating chromatin accessibility.
• Increased numbers of ACLY+p300+ memory astrocytes were observed in EAE models and human MS lesions, correlating with disease severity.
• Genetic inactivation of ACLY+p300+ astrocytes ameliorated EAE pathology.

Conclusions:

• A distinct, epigenetically controlled memory astrocyte subset exacerbates CNS pathology in EAE and potentially MS.
• ACLY and p300 are key regulators of astrocyte memory and pro-inflammatory responses.
• Targeting ACLY+p300+ memory astrocytes presents a potential therapeutic avenue for multiple sclerosis and other neurologic diseases.