title: Ikaros mediates the DNA methylation-independent silencing of MCJ/DNAJC15 gene expression in macrophages.
abstract: MCJ (DNAJC15) is a mitochondrial protein that regulates the mitochondrial metabolic status of macrophages and their response to inflammatory stimuli. CpG island methylation in cancer cells constitutes the only mechanism identified for the regulation of MCJ gene expression. However, whether DNA methylation or transcriptional regulation mechanisms are involved in the physiological control of this gene expression in non-tumor cells remains unknown. We now demonstrate a mechanism of regulation of MCJ expression that is independent of DNA methylation. IFNγ, a protective cytokine against cardiac inflammation during Lyme borreliosis, represses MCJ transcription in macrophages. The transcriptional regulator, Ikaros, binds to the MCJ promoter in a Casein kinase II-dependent manner, and mediates the repression of MCJ expression. These results identify the MCJ gene as a transcriptional target of IFNγ and provide evidence of the dynamic adaptation of normal tissues to changes in the environment as a way to adapt metabolically to new conditions.
authors.affiliation: Department of Veterinary and Animal Sciences. University of Massachusetts Amherst. Amherst, MA 01003.|CIC bioGUNE. 48160 Derio, Bizkaia, Spain.
authors.forename: Nicolás
authors.initials: N
authors.lastname: Navasa
authors.affiliation: CIC bioGUNE. 48160 Derio, Bizkaia, Spain.
authors.forename: Itziar
authors.initials: I
authors.lastname: Martin-Ruiz
authors.affiliation: CIC bioGUNE. 48160 Derio, Bizkaia, Spain.
authors.forename: Estíbaliz
authors.initials: E
authors.lastname: Atondo
authors.affiliation: CIC bioGUNE. 48160 Derio, Bizkaia, Spain.
authors.forename: James D
authors.initials: JD
authors.lastname: Sutherland
authors.affiliation: CIC bioGUNE. 48160 Derio, Bizkaia, Spain.
authors.forename: Miguel
authors.initials: M
authors.lastname: Angel Pascual-Itoiz
authors.affiliation: CIC bioGUNE. 48160 Derio, Bizkaia, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Carreras-González
authors.affiliation: Department of Veterinary and Animal Sciences. University of Massachusetts Amherst. Amherst, MA 01003.
authors.forename: Hooman
authors.initials: H
authors.lastname: Izadi
authors.affiliation: CIC bioGUNE. 48160 Derio, Bizkaia, Spain.
authors.forename: Julen
authors.initials: J
authors.lastname: Tomás-Cortázar
authors.affiliation: Department of Veterinary and Animal Sciences. University of Massachusetts Amherst. Amherst, MA 01003.
authors.forename: Furkan
authors.initials: F
authors.lastname: Ayaz
authors.affiliation: CIC bioGUNE. 48160 Derio, Bizkaia, Spain.
authors.forename: Natalia
authors.initials: N
authors.lastname: Martin-Martin
authors.affiliation: Department of Veterinary and Animal Sciences. University of Massachusetts Amherst. Amherst, MA 01003.
authors.forename: Iviana M
authors.initials: IM
authors.lastname: Torres
authors.affiliation: CIC bioGUNE. 48160 Derio, Bizkaia, Spain.
authors.forename: Rosa
authors.initials: R
authors.lastname: Barrio
authors.affiliation: CIC bioGUNE. 48160 Derio, Bizkaia, Spain.|Ikerbasque, Basque Foundation for Science. 48011 Bilbao, Bizkaia, Spain.|Biochemistry and Molecular Biology Department, University of the Basque Country (UPV/EHU), P. O. Box 644, E-48080 Bilbao, Spain.
authors.forename: Arkaitz
authors.initials: A
authors.lastname: Carracedo
authors.affiliation: Department of Molecular Biology, Veterinary School, University of León. 24071 León, Spain.
authors.forename: Elias R
authors.initials: ER
authors.lastname: Olivera
authors.affiliation: Department of Medicine. University of Vermont College of Medicine. Burlington, VT 05405.
authors.forename: Mercedes
authors.initials: M
authors.lastname: Rincón
authors.affiliation: Department of Veterinary and Animal Sciences. University of Massachusetts Amherst. Amherst, MA 01003.|CIC bioGUNE. 48160 Derio, Bizkaia, Spain.|Ikerbasque, Basque Foundation for Science. 48011 Bilbao, Bizkaia, Spain.
authors.forename: Juan
authors.initials: J
authors.lastname: Anguita
mesh_terms: D000818:Animals; D001483:Base Sequence; D025065:Borrelia burgdorferi; D047390:Casein Kinase II / Q000378:metabolism; D019175:DNA Methylation; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D020868:Gene Silencing; D051740:Ikaros Transcription Factor / Q000378:metabolism*; D007371:Interferon-gamma / Q000494:pharmacology; D008264:Macrophages / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D024101:Mitochondrial Proteins / Q000235:genetics*; D018832:Molecular Chaperones / Q000235:genetics*; D008969:Molecular Sequence Data; D009205:Myocarditis / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D014158:Transcription, Genetic; D015533:Transcriptional Activation
chemical_list: C582292:Mcj protein, mouse; D024101:Mitochondrial Proteins; D018832:Molecular Chaperones; D051740:Ikaros Transcription Factor; D007371:Interferon-gamma; D047390:Casein Kinase II