The Transcriptional Cofactor Nab2 Is Induced by TGF-β and Suppresses Fibroblast Activation: Physiological Roles and Impaired Expression in Scleroderma

• DOI: 10.1371/journal.pone.0007620
• Publication Date: 2009-10-23T17:18:07Z
• Authors: Swati Bhattacharyya; Jun Wei; Denisa S. Melichian; Jeffrey Milbrandt; Kazuhiko Takehara; John Varga
• Keywords: Periostin; Myofibroblast

By stimulating collagen synthesis and myofibroblasts differentiation, transforming growth factor-β (TGF- β) plays a pivotal role in tissue repair fibrosis. The early response-1 (Egr-1) transcription factor mediates profibrotic TGF-β responses, its expression is elevated biopsies from patients with scleroderma. NGF1-A-binding protein 2 (Nab2) conserved transcriptional cofactor that directly binds to Egr-1 positively or negatively modulates target gene transcription. Despite the recognized importance of Nab2 governing intensity Egr-1-dependent regulation function context fibrotic signaling unknown. Here we show caused time-dependent stimulation mRNA normal fibroblasts. Ectopic these cells blocked abrogated TGF-β-induced differentiation. These inhibitory effects involved recruitment NuRD chromatin remodeling complex COL1A2 promoter were accompanied by reduced histone H4 acetylation. Mice targeted deletion displayed increased accumulation dermis, genetic siRNA-mediated loss fibroblasts was associated constitutively accentuation responses vitro. Expression markedly up-regulated skin scleroderma, localized primarily epidermal keratinocytes. In contrast, little could be detected dermal results identify as novel endogenous negative regulator responsible for setting responses. Defective might play persistent