The histone demethylase PHF8 regulates astrocyte differentiation and function

Simona Iacobucci,Claudia Verderio,Martina Gabrielli,Marian A Martínez-Balbás,Marta Vicioso-Mantis,Natalia Padilla,Claudia Navarro,Marta Lombardi,Xavier De La Cruz

doi:10.1242/dev.194951

Abstract

Epigenetic factors have been shown to play a crucial role in X-linked intellectual disability (XLID). Here, we investigate the contribution of the XLID-associated histone demethylase PHF8 to astrocyte differentiation and function. Using genome-wide analyses and biochemical assays, we reveal a regulatory crosstalk between PHF8 and Notch signaling pathway that balances the expression of the master astrocytic gene Nfia. Moreover, PHF8 regulates key synaptic genes in astrocytes by keeping low levels of H4K20me3. Accordingly, astrocytic-PHF8 depletion has a striking effect on neuronal synapse formation and maturation in vitro. These data reveal that PHF8 is crucial in astrocyte development to maintain the chromatin homeostasis and limiting the heterochromatin formation at synaptogenic genes. Our studies suggest a new paradigm for the implication of epigenetics in intellectual disability.

Highlights

X-linked intellectual disability (XLID) includes a diverse group of cognitive disorders ranging from mild intellectual deficits to severe cognitive impairments (Chelly et al, 2006; Ropers and Hamel, 2005)
To evaluate the functional relevance of PHF8 during astrocyte differentiation, we isolated neural stem cells (NSCs) from cortices of mouse embryos at embryonic day (E) 12.5 (Estaras et al, 2012; Sun et al, 2001) and differentiated them to astrocytes following the protocol described in the Materials and Methods (Fig. 1B)
Our study reveals an unexpected role of the XLID gene Phf8 in astrocytes, the most abundant glial cells in the mammalian brain

Summary

Introduction

X-linked intellectual disability (XLID) includes a diverse group of cognitive disorders ranging from mild intellectual deficits to severe cognitive impairments (Chelly et al, 2006; Ropers and Hamel, 2005). Intellectual disability (ID), as well as other neurodevelopmental disorders, is characterized by anomalies in the establishment and function of synaptic circuits. ID research focused mainly on neurons, astrocytes make a crucial contribution to synapse formation (Cresto et al, 2019; McGann et al, 2012), maturation and elimination (Araque et al, 2014). Recently have genetic studies underscored the potential role of astrocytes in neurodevelopmental disorders, such as Down, Rett and Fragile X syndromes (Cresto et al, 2019). Astrocyte contribution to ID is still largely unexplored. Large-scale genetic analyses revealed that a strikingly considerable number of genes mutated in XLID encode regulators

Methods

Results

Conclusion