Alternative Splicing of G9a Regulates Neuronal Differentiation

Chromatin modifications are critical for the establishment and maintenance of differentiation programs. G9a, the enzyme responsible for histone H3 lysine 9 dimethylation in mammalian euchromatin, exists as two isoforms with differential inclusion of exon 10 (E10) through alternative splicing. We fin...

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Autores principales: Fiszbein, Ana, Giono, Luciana Eugenia, Quaglino, Ana, Sigaut, Lorena, von Bilderling, Catalina, Schor, Ignacio Esteban, Rossi, Mario, Srebrow, Anabella, Kornblihtt, Alberto Rodolfo
Publicado: 2016
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Acceso en línea:https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_22111247_v14_n12_p2797_Fiszbein
http://hdl.handle.net/20.500.12110/paper_22111247_v14_n12_p2797_Fiszbein
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Sumario:Chromatin modifications are critical for the establishment and maintenance of differentiation programs. G9a, the enzyme responsible for histone H3 lysine 9 dimethylation in mammalian euchromatin, exists as two isoforms with differential inclusion of exon 10 (E10) through alternative splicing. We find that the G9a methyltransferase is required for differentiation of the mouse neuronal cell line N2a and that E10 inclusion increases during neuronal differentiation of cultured cells, as well as in the developing mouse brain. Although E10 inclusion greatly stimulates overall H3K9me2 levels, it does not affect G9a catalytic activity. Instead, E10 increases G9a nuclear localization. We show that the G9a E10+ isoform is necessary for neuron differentiation and regulates the alternative splicing pattern of its own pre-mRNA, enhancing E10 inclusion. Overall, our findings indicate that by regulating its own alternative splicing, G9a promotes neuron differentiation and creates a positive feedback loop that reinforces cellular commitment to differentiation. Fiszbein et al. show that the histone methyltransferase G9a regulates alternative splicing of its own transcript, an event critical for neuron differentiation. Inclusion of exon 10 stimulates H3K9me2 levels and promotes nuclear localization of G9a, creating a positive feedback loop that reinforces the cellular commitment to differentiation. © 2016 The Authors.