title: SWI/SNF deficiency results in aberrant chromatin organization, mitotic failure, and diminished proliferative capacity.
abstract: Switch (SWI)/sucrose nonfermentable (SNF) is an evolutionarily conserved complex with ATPase function, capable of regulating nucleosome position to alter transcriptional programs within the cell. It is known that the SWI/SNF complex is responsible for regulation of many genes involved in cell cycle control and proliferation, and it has recently been implicated in cancer development. The ATPase action of SWI/SNF is conferred through either the brahma-related gene 1 (Brg1) or brahma (Brm) subunit of the complex, and it is of central importance to the modification of nucleosome position. In this study, the role of the Brg1 and Brm subunits were examined as they relate to chromatin structure and organization. Deletion of the Brg1 ATPase results in dissolution of pericentromeric heterochromatin domains and a redistribution of histone modifications associated with these structures. This effect was highly specific to Brg1 and is not reproduced by the loss of Brm or SNF5/BAF47/INI1. Brg1 deficiency is associated with the appearance of micronuclei and aberrant mitoses that are a by-product of dissociated chromatin structure. Thus, Brg1 plays a critical role in maintaining chromatin structural integrity.
authors.affiliation: *Department of Cancer Biology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA. ryan.bourgo@jefferson.edu
authors.forename: Ryan J
authors.initials: RJ
authors.lastname: Bourgo
authors.forename: Hasan
authors.initials: H
authors.lastname: Siddiqui
authors.forename: Sejal
authors.initials: S
authors.lastname: Fox
authors.forename: David
authors.initials: D
authors.lastname: Solomon
authors.forename: Courtney G
authors.initials: CG
authors.lastname: Sansam
authors.forename: Moshe
authors.initials: M
authors.lastname: Yaniv
authors.forename: Christian
authors.initials: C
authors.lastname: Muchardt
authors.forename: Daniel
authors.initials: D
authors.lastname: Metzger
authors.forename: Pierre
authors.initials: P
authors.lastname: Chambon
authors.forename: Charles W M
authors.initials: CW
authors.lastname: Roberts
authors.forename: Erik S
authors.initials: ES
authors.lastname: Knudsen
mesh_terms: D016475:3T3 Cells; D000782:Aneuploidy; D000818:Animals; D002467:Cell Nucleus / Q000201:enzymology / Q000473:pathology; D049109:Cell Proliferation; D002843:Chromatin / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D004265:DNA Helicases / Q000172:deficiency* / Q000378:metabolism; D005347:Fibroblasts / Q000201:enzymology / Q000473:pathology; D017353:Gene Deletion; D018390:Gene Targeting; D016678:Genome / Q000235:genetics; D006657:Histones / Q000378:metabolism; D008745:Methylation; D051379:Mice; D008938:Mitosis; D009687:Nuclear Proteins / Q000172:deficiency* / Q000378:metabolism; D014157:Transcription Factors / Q000172:deficiency* / Q000378:metabolism
chemical_list: D002843:Chromatin; D006657:Histones; D009687:Nuclear Proteins; C499503:Smarca2 protein, mouse; D014157:Transcription Factors; C513194:Smarca4 protein, mouse; D004265:DNA Helicases