title: Id2 complexes with the SNAG domain of Snai1 inhibiting Snai1-mediated repression of integrin β4.
abstract: The epithelial-mesenchymal transition (EMT) is a fundamental process that underlies development and cancer. Although the EMT involves alterations in the expression of specific integrins that mediate stable adhesion to the basement membrane, such as α6β4, the mechanisms involved are poorly understood. Here, we report that Snai1 inhibits β4 transcription by increasing repressive histone modification (trimethylation of histone H3 at K27 [H3K27Me3]). Surprisingly, Snai1 is expressed and localized in the nucleus in epithelial cells, but it does not repress β4. We resolved this paradox by discovering that Id2 complexes with the SNAG domain of Snai1 on the β4 promoter and constrains the repressive function of Snai1. Disruption of the complex by depleting Id2 resulted in Snai1-mediated β4 repression with a concomitant increase in H3K27Me3 modification on the β4 promoter. These findings establish a novel function for Id2 in regulating Snai1 that has significant implications for the regulation of epithelial gene expression.
authors.affiliation: University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors.forename: Cheng
authors.initials: C
authors.lastname: Chang
authors.forename: Xiaofang
authors.initials: X
authors.lastname: Yang
authors.forename: Bryan
authors.initials: B
authors.lastname: Pursell
authors.forename: Arthur M
authors.initials: AM
authors.lastname: Mercurio
mesh_terms: D000818:Animals; D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects / Q000235:genetics; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D006657:Histones / Q000378:metabolism*; D006801:Humans; D051797:Inhibitor of Differentiation Protein 2 / Q000235:genetics / Q000378:metabolism*; D039663:Integrin beta4 / Q000235:genetics / Q000378:metabolism*; D008239:Lysine / Q000378:metabolism; D061986:MCF-7 Cells; D008745:Methylation; D051379:Mice; D008969:Molecular Sequence Data; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012689:Sequence Homology, Nucleic Acid; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology
chemical_list: D015820:Cadherins; D006657:Histones; C497452:Idb2 protein, mouse; D051797:Inhibitor of Differentiation Protein 2; D039663:Integrin beta4; C000604407:SNAI1 protein, human; C000604429:Snai1 protein, mouse; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D053773:Transforming Growth Factor beta1; D008239:Lysine