Histone deacetylase 3 associates with MeCP2 to regulate FOXO and social behavior

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• Mutations in MECP2 cause Rett syndrome (RTT), a neurodevelopmental disorder.
• The RTT-associated MECP2^R306C mutation disrupts the interaction between MeCP2 and the histone deacetylase 3 (HDAC3) complex.
• The specific role of HDAC3 in neuronal function remains unclear.

Purpose of the Study:

• To investigate the neuronal function of HDAC3.
• To elucidate the role of HDAC3 in MeCP2-mediated gene regulation.
• To understand the contribution of HDAC3 disruption to RTT pathogenesis.

Main Methods:

• Neuronal deletion of Hdac3 in mice.
• Transcriptional and chromatin profiling.
• Analysis of MeCP2^R306C patient-derived neural progenitor cells and isogenic controls using gene editing.

Main Results:

• Neuronal Hdac3 deletion in mice caused deficits in motor coordination, sociability, and cognition.
• HDAC3 positively regulates a subset of neuronal genes and is recruited to promoters via MeCP2.
• HDAC3-associated promoters are enriched for FOXO transcription factors; FOXO acetylation increased in Hdac3 and Mecp2 knockout neurons.
• MECP2^R306C patient cells showed impaired HDAC3 and FOXO recruitment and gene expression, which was rescued by gene editing.

Conclusions:

• HDAC3, through interaction with MeCP2, positively regulates neuronal gene expression via FOXO deacetylation.
• Disruption of HDAC3 function contributes to the cognitive and social impairments observed in RTT.
• Targeting HDAC3-FOXO pathways may offer therapeutic potential for RTT.