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...
Main Authors: | , , , , , , , , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
Elsevier
2016-03-01
|
Series: | Cell Reports |
Online Access: | http://www.sciencedirect.com/science/article/pii/S221112471630184X |
id |
doaj-0654f5f243734f53950886972593361e |
---|---|
record_format |
Article |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Ana Fiszbein Luciana E. Giono Ana Quaglino Bruno G. Berardino Lorena Sigaut Catalina von Bilderling Ignacio E. Schor Juliana H. Enriqué Steinberg Mario Rossi Lía I. Pietrasanta Julio J. Caramelo Anabella Srebrow Alberto R. Kornblihtt |
spellingShingle |
Ana Fiszbein Luciana E. Giono Ana Quaglino Bruno G. Berardino Lorena Sigaut Catalina von Bilderling Ignacio E. Schor Juliana H. Enriqué Steinberg Mario Rossi Lía I. Pietrasanta Julio J. Caramelo Anabella Srebrow Alberto R. Kornblihtt Alternative Splicing of G9a Regulates Neuronal Differentiation Cell Reports |
author_facet |
Ana Fiszbein Luciana E. Giono Ana Quaglino Bruno G. Berardino Lorena Sigaut Catalina von Bilderling Ignacio E. Schor Juliana H. Enriqué Steinberg Mario Rossi Lía I. Pietrasanta Julio J. Caramelo Anabella Srebrow Alberto R. Kornblihtt |
author_sort |
Ana Fiszbein |
title |
Alternative Splicing of G9a Regulates Neuronal Differentiation |
title_short |
Alternative Splicing of G9a Regulates Neuronal Differentiation |
title_full |
Alternative Splicing of G9a Regulates Neuronal Differentiation |
title_fullStr |
Alternative Splicing of G9a Regulates Neuronal Differentiation |
title_full_unstemmed |
Alternative Splicing of G9a Regulates Neuronal Differentiation |
title_sort |
alternative splicing of g9a regulates neuronal differentiation |
publisher |
Elsevier |
series |
Cell Reports |
issn |
2211-1247 |
publishDate |
2016-03-01 |
description |
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. |
url |
http://www.sciencedirect.com/science/article/pii/S221112471630184X |
work_keys_str_mv |
AT anafiszbein alternativesplicingofg9aregulatesneuronaldifferentiation AT lucianaegiono alternativesplicingofg9aregulatesneuronaldifferentiation AT anaquaglino alternativesplicingofg9aregulatesneuronaldifferentiation AT brunogberardino alternativesplicingofg9aregulatesneuronaldifferentiation AT lorenasigaut alternativesplicingofg9aregulatesneuronaldifferentiation AT catalinavonbilderling alternativesplicingofg9aregulatesneuronaldifferentiation AT ignacioeschor alternativesplicingofg9aregulatesneuronaldifferentiation AT julianahenriquesteinberg alternativesplicingofg9aregulatesneuronaldifferentiation AT mariorossi alternativesplicingofg9aregulatesneuronaldifferentiation AT liaipietrasanta alternativesplicingofg9aregulatesneuronaldifferentiation AT juliojcaramelo alternativesplicingofg9aregulatesneuronaldifferentiation AT anabellasrebrow alternativesplicingofg9aregulatesneuronaldifferentiation AT albertorkornblihtt alternativesplicingofg9aregulatesneuronaldifferentiation |
_version_ |
1724978508307890176 |
spelling |
doaj-0654f5f243734f53950886972593361e2020-11-25T01:56:42ZengElsevierCell Reports2211-12472016-03-0114122797280810.1016/j.celrep.2016.02.063Alternative Splicing of G9a Regulates Neuronal DifferentiationAna Fiszbein0Luciana E. Giono1Ana Quaglino2Bruno G. Berardino3Lorena Sigaut4Catalina von Bilderling5Ignacio E. Schor6Juliana H. Enriqué Steinberg7Mario Rossi8Lía I. Pietrasanta9Julio J. Caramelo10Anabella Srebrow11Alberto R. Kornblihtt12Departamento de Fisiología, Biología Molecular y Celular, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires and Instituto de Fisiología, Biología Molecular y Neurociencias (IFIBYNE-CONICET), Ciudad Universitaria Pabellón II, C1428EHA Buenos Aires, ArgentinaDepartamento de Fisiología, Biología Molecular y Celular, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires and Instituto de Fisiología, Biología Molecular y Neurociencias (IFIBYNE-CONICET), Ciudad Universitaria Pabellón II, C1428EHA Buenos Aires, ArgentinaDepartamento de Fisiología, Biología Molecular y Celular, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires and Instituto de Fisiología, Biología Molecular y Neurociencias (IFIBYNE-CONICET), Ciudad Universitaria Pabellón II, C1428EHA Buenos Aires, ArgentinaDepartamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad Universitaria Pabellón II, C1428EHA Buenos Aires, ArgentinaDepartamento de Física, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires and IFIBA-CONICET, Cuidad Universitaria Pabellón I, C1428EHA Buenos Aires, ArgentinaDepartamento de Física, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires and IFIBA-CONICET, Cuidad Universitaria Pabellón I, C1428EHA Buenos Aires, ArgentinaDepartamento de Fisiología, Biología Molecular y Celular, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires and Instituto de Fisiología, Biología Molecular y Neurociencias (IFIBYNE-CONICET), Ciudad Universitaria Pabellón II, C1428EHA Buenos Aires, ArgentinaInstituto de Investigación en Biomedicina de Buenos Aires CONICET, Partner Institute of the Max Planck Society, C1425FQD Buenos Aires, ArgentinaInstituto de Investigación en Biomedicina de Buenos Aires CONICET, Partner Institute of the Max Planck Society, C1425FQD Buenos Aires, ArgentinaDepartamento de Física, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires and IFIBA-CONICET, Cuidad Universitaria Pabellón I, C1428EHA Buenos Aires, ArgentinaDepartamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad Universitaria Pabellón II, C1428EHA Buenos Aires, ArgentinaDepartamento de Fisiología, Biología Molecular y Celular, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires and Instituto de Fisiología, Biología Molecular y Neurociencias (IFIBYNE-CONICET), Ciudad Universitaria Pabellón II, C1428EHA Buenos Aires, ArgentinaDepartamento de Fisiología, Biología Molecular y Celular, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires and Instituto de Fisiología, Biología Molecular y Neurociencias (IFIBYNE-CONICET), Ciudad Universitaria Pabellón II, C1428EHA Buenos Aires, ArgentinaChromatin 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.http://www.sciencedirect.com/science/article/pii/S221112471630184X |