title: Control of genetic stability by a new heterochromatin compaction pathway involving the Tip60 histone acetyltransferase.
abstract: Pericentric heterochromatin is a highly compacted structure required for accurate chromosome segregation in mitosis. In mammals, it relies on methylation of histone H3K9 by Suv39H enzymes, which provides a docking site for HP1 proteins, therefore mediating heterochromatin compaction. Here we show that, when this normal compaction pathway is defective, the histone acetyltransferase Tip60 is recruited to pericentric heterochromatin, where it mediates acetylation of histone H4K12. Furthermore, in such a context, depletion of Tip60 leads to derepression of satellite transcription, decompaction of pericentric heterochromatin, and defects in chromosome segregation in mitosis. Finally, we show that depletion of BRD2, a double bromodomain-containing protein that binds H4K12ac, phenocopies the Tip60 depletion with respect to heterochromatin decompaction and defects in chromosome segregation. Taking the results together, we identify a new compaction pathway of mammalian pericentric heterochromatin relying on Tip60 that might be dependent on BRD2 recruitment by H4K12 acetylation. We propose that the underexpression of Tip60 observed in many human tumors can promote genetic instability via defective pericentric heterochromatin.
authors.affiliation: Laboratoire de Biologie Cellulaire et Moléculaire du Contrôle de la Prolifération, Center for Integrative Biology, Université de Toulouse, UPS and CNRS, F-31062 Toulouse, France.
authors.forename: Aude
authors.initials: A
authors.lastname: Grézy
authors.affiliation: Laboratoire de Biologie Cellulaire et Moléculaire du Contrôle de la Prolifération, Center for Integrative Biology, Université de Toulouse, UPS and CNRS, F-31062 Toulouse, France.
authors.forename: Martine
authors.initials: M
authors.lastname: Chevillard-Briet
authors.affiliation: Laboratoire de Biologie Cellulaire et Moléculaire du Contrôle de la Prolifération, Center for Integrative Biology, Université de Toulouse, UPS and CNRS, F-31062 Toulouse, France.
authors.forename: Didier
authors.initials: D
authors.lastname: Trouche
authors.affiliation: Laboratoire de Biologie Cellulaire et Moléculaire du Contrôle de la Prolifération, Center for Integrative Biology, Université de Toulouse, UPS and CNRS, F-31062 Toulouse, France fabrice.escaffit@univ-tlse3.fr.
authors.forename: Fabrice
authors.initials: F
authors.lastname: Escaffit
mesh_terms: D000107:Acetylation; D000818:Animals; D000090266:Chromobox Protein Homolog 5; D043171:Chromosomal Instability / Q000235:genetics*; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics / Q000378:metabolism*; D020090:Chromosome Segregation / Q000235:genetics; D006570:Heterochromatin / Q000378:metabolism*; D051548:Histone Acetyltransferases / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000378:metabolism*; D000074443:Lysine Acetyltransferase 5; D008745:Methylation; D008780:Methyltransferases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008938:Mitosis / Q000235:genetics; D041681:NIH 3T3 Cells; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors; D000092468:Bromodomain Containing Proteins
chemical_list: D000090266:Chromobox Protein Homolog 5; D002868:Chromosomal Proteins, Non-Histone; D006570:Heterochromatin; D051548:Histone Acetyltransferases; D006657:Histones; D000074443:Lysine Acetyltransferase 5; D008780:Methyltransferases; D034741:RNA, Small Interfering; D012097:Repressor Proteins; D015534:Trans-Activators; D014157:Transcription Factors; C490844:Brd2 protein, mouse; D000092468:Bromodomain Containing Proteins; C498700:Suv39h1 protein, mouse; C523065:Kat5 protein, mouse