title: Network Analysis Identifies Mitochondrial Regulation of Epidermal Differentiation by MPZL3 and FDXR.
abstract: Current gene expression network approaches commonly focus on transcription factors (TFs), biasing network-based discovery efforts away from potentially important non-TF proteins. We developed proximity analysis, a network reconstruction method that uses topological constraints of scale-free, small-world biological networks to reconstruct relationships in eukaryotic systems, independent of subcellular localization. Proximity analysis identified MPZL3 as a highly connected hub that is strongly induced during epidermal differentiation. MPZL3 was essential for normal differentiation, acting downstream of p63, ZNF750, KLF4, and RCOR1, each of which bound near the MPZL3 gene and controlled its expression. MPZL3 protein localized to mitochondria, where it interacted with FDXR, which was itself also found to be essential for differentiation. Together, MPZL3 and FDXR increased reactive oxygen species (ROS) to drive epidermal differentiation. ROS-induced differentiation is dependent upon promotion of FDXR enzymatic activity by MPZL3. ROS induction by the MPZL3 and FDXR mitochondrial proteins is therefore essential for epidermal differentiation.
authors.affiliation: Program in Epithelial Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Aparna
authors.initials: A
authors.lastname: Bhaduri
authors.affiliation: Program in Epithelial Biology, Stanford University School of Medicine, Stanford, CA 94305, USA; Division of Hematology, Stanford University, Stanford, CA 94305, USA.
authors.forename: Alexander
authors.initials: A
authors.lastname: Ungewickell
authors.affiliation: Program in Epithelial Biology, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Biology, Stanford University, Stanford, CA 94305, USA.
authors.forename: Lisa D
authors.initials: LD
authors.lastname: Boxer
authors.affiliation: Program in Epithelial Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Lopez-Pajares
authors.affiliation: Program in Epithelial Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Zarnegar
authors.affiliation: Program in Epithelial Biology, Stanford University School of Medicine, Stanford, CA 94305, USA; Veterans Affairs Palo Alto Healthcare System, Palo Alto, CA 94304, USA. Electronic address: khavari@stanford.edu.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Khavari
mesh_terms: D002454:Cell Differentiation; D002478:Cells, Cultured; D000078404:Epidermal Cells; D004817:Epidermis / Q000378:metabolism; D005287:Ferredoxin-NADP Reductase / Q000235:genetics / Q000378:metabolism*; D005288:Ferredoxins / Q000378:metabolism; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D006801:Humans; D015603:Keratinocytes / Q000166:cytology* / Q000378:metabolism; D000090062:Kruppel-Like Factor 4; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D055432:Metabolomics; D008928:Mitochondria / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D005288:Ferredoxins; C000715467:KLF4 protein, human; D000090062:Kruppel-Like Factor 4; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; C542811:Mpzl3 protein, human; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D014157:Transcription Factors; D005287:Ferredoxin-NADP Reductase
keywords: FDXR; MPZL3; differentiation; mitochondria; network biology