Regulation of heterochromatin transcription by Snail1/LOXL2 during epithelial-to-mesenchymal transition.
Although heterochromatin is enriched with repressive traits, it is also actively transcribed, giving rise to large amounts of noncoding RNAs. Although these RNAs are responsible for the formation and maintenance of heterochromatin, little is known about how their transcription is regulated. Here, we show that the Snail1 transcription factor represses mouse pericentromeric transcription, acting through the H3K4 deaminase LOXL2. Since Snail1 plays a key role in the epithelial-to-mesenchymal transition (EMT), we analyzed the regulation of heterochromatin transcription in this process. At the onset of EMT, one of the major structural heterochromatin proteins, HP1α, is transiently released from heterochromatin foci in a Snail1/LOXL2-dependent manner, concomitantly with a downregulation of major satellite transcription. Moreover, preventing the downregulation of major satellite transcripts compromised the migratory and invasive behavior of mesenchymal cells. We propose that Snail1 regulates heterochromatin transcription through LOXL2, thus creating the favorable transcriptional state necessary for completing EMT.
Programa de Recerca en Càncer, Institut Hospital del Mar d'Investigacions Mèdiques (IMIM), 08003 Barcelona, Spain.
Alba
A
Millanes-Romero
Cell Proliferation Group, MRC Clinical Sciences Centre, Faculty of Medicine, Imperial College, W12 0NN London, UK.
Nicolás
N
Herranz
Max Planck Institute of Immunology and Epigenetics, 79108 Freiburg, Germany.
Valentina
V
Perrera
Programa de Recerca en Càncer, Institut Hospital del Mar d'Investigacions Mèdiques (IMIM), 08003 Barcelona, Spain.
Ane
A
Iturbide
Programa de Recerca en Càncer, Institut Hospital del Mar d'Investigacions Mèdiques (IMIM), 08003 Barcelona, Spain.
Jordina
J
Loubat-Casanovas
Cell Proliferation Group, MRC Clinical Sciences Centre, Faculty of Medicine, Imperial College, W12 0NN London, UK.
Jesús
J
Gil
Max Planck Institute of Immunology and Epigenetics, 79108 Freiburg, Germany.
Thomas
T
Jenuwein
Programa de Recerca en Càncer, Institut Hospital del Mar d'Investigacions Mèdiques (IMIM), 08003 Barcelona, Spain; Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, 08003 Barcelona, Spain.
Antonio
A
García de Herreros
Programa de Recerca en Càncer, Institut Hospital del Mar d'Investigacions Mèdiques (IMIM), 08003 Barcelona, Spain. Electronic address: speiro@imim.es.
Sandra
S
Peiró
D000594:Amino Acid Oxidoreductases / Q000235:genetics*; D000818:Animals; D002460:Cell Line; D000090266:Chromobox Protein Homolog 5; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics; D015536:Down-Regulation; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D057809:HEK293 Cells; D006570:Heterochromatin / Q000235:genetics*; D006657:Histones / Q000235:genetics; D006801:Humans; D008648:Mesoderm / Q000378:metabolism; D051379:Mice; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000235:genetics*; D014158:Transcription, Genetic
C000715594:CBX5 protein, human; D002868:Chromosomal Proteins, Non-Histone; D006570:Heterochromatin; D006657:Histones; C000604407:SNAI1 protein, human; C000604429:Snai1 protein, mouse; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D000090266:Chromobox Protein Homolog 5; D000594:Amino Acid Oxidoreductases; C485601:Loxl2 protein, mouse