title: Alternative Splicing of G9a Regulates Neuronal Differentiation.
abstract: 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.
authors.affiliation: Departamento 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, Argentina.
authors.forename: Ana
authors.initials: A
authors.lastname: Fiszbein
authors.affiliation: Departamento 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, Argentina.
authors.forename: Luciana E
authors.initials: LE
authors.lastname: Giono
authors.affiliation: Departamento 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, Argentina.
authors.forename: Ana
authors.initials: A
authors.lastname: Quaglino
authors.affiliation: Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad Universitaria Pabellón II, C1428EHA Buenos Aires, Argentina.
authors.forename: Bruno G
authors.initials: BG
authors.lastname: Berardino
authors.affiliation: Departamento de Física, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires and IFIBA-CONICET, Cuidad Universitaria Pabellón I, C1428EHA Buenos Aires, Argentina.
authors.forename: Lorena
authors.initials: L
authors.lastname: Sigaut
authors.affiliation: Departamento de Física, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires and IFIBA-CONICET, Cuidad Universitaria Pabellón I, C1428EHA Buenos Aires, Argentina.
authors.forename: Catalina
authors.initials: C
authors.lastname: von Bilderling
authors.affiliation: Departamento 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, Argentina.
authors.forename: Ignacio E
authors.initials: IE
authors.lastname: Schor
authors.affiliation: Instituto de Investigación en Biomedicina de Buenos Aires CONICET, Partner Institute of the Max Planck Society, C1425FQD Buenos Aires, Argentina.
authors.forename: Juliana H
authors.initials: JH
authors.lastname: Enriqué Steinberg
authors.affiliation: Instituto de Investigación en Biomedicina de Buenos Aires CONICET, Partner Institute of the Max Planck Society, C1425FQD Buenos Aires, Argentina.
authors.forename: Mario
authors.initials: M
authors.lastname: Rossi
authors.affiliation: Departamento de Física, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires and IFIBA-CONICET, Cuidad Universitaria Pabellón I, C1428EHA Buenos Aires, Argentina; Centro de Microscopías Avanzadas, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Cuidad Universitaria, C1428EHA Buenos Aires, Argentina.
authors.forename: Lía I
authors.initials: LI
authors.lastname: Pietrasanta
authors.affiliation: Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad Universitaria Pabellón II, C1428EHA Buenos Aires, Argentina; Fundación Instituto Leloir, C1405BWE Buenos Aires, Argentina.
authors.forename: Julio J
authors.initials: JJ
authors.lastname: Caramelo
authors.affiliation: Departamento 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, Argentina.
authors.forename: Anabella
authors.initials: A
authors.lastname: Srebrow
authors.affiliation: Departamento 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, Argentina. Electronic address: ark@fbmc.fcen.uba.ar.
authors.forename: Alberto R
authors.initials: AR
authors.lastname: Kornblihtt
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D001381:Azepines / Q000494:pharmacology; D001921:Brain / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D005091:Exons; D031541:Fluorescence Resonance Energy Transfer; D017930:Genes, Reporter; D006367:HeLa Cells; D011495:Histone-Lysine N-Methyltransferase / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D008745:Methylation / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008856:Microscopy, Fluorescence; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology; D034622:RNA Interference; D012322:RNA Precursors / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D014212:Tretinoin / Q000494:pharmacology
chemical_list: D001381:Azepines; C518299:BIX 01294; D006657:Histones; D020033:Protein Isoforms; D011799:Quinazolines; D012322:RNA Precursors; D034741:RNA, Small Interfering; D014212:Tretinoin; D011495:Histone-Lysine N-Methyltransferase