Alternative Splicing of G9a Regulates Neuronal Differentiation

FISZBEIN, ANA; GIONO, LUCIANA E; QUAGLINO, ANA; BERNARDINO, BRUNO G; SIGAUT, LORENA; VON BILDERLING, CATALINA; SCHOR, IGNACIO E; ENRIQUÉ STEINBERG, JULIANA H; ROSSI, MARIO; PIETRASANTA, LIA I; CARAMELO, JULIO J; SREBROW, ANABELLA; KORNBLIHTT, ALBERTO R.

Cell Reports

Cell Press

Año: 2016 vol. 14 p. 2797 - 2808

Chromatin modifications are critical for the establishment and maintenance ofdifferentiation programs. G9a, the enzyme responsible for histone H3 lysine 9dimethylation in mammalian euchromatin, exists as two isoforms with differential inclusion of exon 10 (E10) through alternative splicing. We find that the G9amethyltransferase is required for differentiation of the mouse neuronal cell lineN2a and that E10 inclusion increases during neuronal differentiation of cultured cells, as well as in the developing mouse brain. Although E10 inclusion greatlystimulates 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 alternativesplicing pattern of its own pre-mRNA, enhancing E10 inclusion. Overall, ourfindings indicate that by regulating its own alternative splicing, G9a promotesneuron differentiation and creates a positive feedback loop that reinforcescellular commitment to differentiation.