The transcriptional cofactor Nab2 Is induced by TGF-beta and suppresses fibroblast activation: Physiological roles and impaired expression in scleroderma

By stimulating collagen synthesis and myofibroblasts differentiation, transforming growth factor-b (TGFb) plays a pivotal role in tissue repair and fibrosis. The early growth response-1 (Egr-1) transcription factor mediates profibrotic TGF-b responses, and its expression is elevated in biopsies from patients with scleroderma. NGF1-A-binding protein 2 (Nab2) is a conserved transcriptional cofactor that directly binds to Egr-1 and positively or negatively modulates Egr-1 target gene transcription. Despite the recognized importance of Nab2 in governing the intensity of Egr-1-dependent responses, the regulation and function of Nab2 in the context of fibrotic TGF-b signaling is unknown. Here we show that TGF-b caused a time-dependent stimulation of Nab2 protein and mRNA in normal fibroblasts. Ectopic expression of Nab2 in these cells blocked Egr-1-dependent transcriptional responses, and abrogated TGF-b-induced stimulation of collagen synthesis and myofibroblasts differentiation. These inhibitory effects of Nab2 involved recruitment of the NuRD chromatin remodeling complex to the COL1A2 promoter and were accompanied by reduced histone H4 acetylation. Mice with targeted deletion of Nab2 displayed increased collagen accumulation in the dermis, and genetic or siRNA-mediated loss of Nab2 in fibroblasts was associated with constitutively elevated collagen synthesis and accentuation of Egr-1-dependent TGF-b responses in vitro. Expression of Nab2 was markedly up-regulated in skin biopsies from patients with scleroderma, and was localized primarily to epidermal keratinocytes. In contrast, little Nab2 could be detected in dermal fibroblasts. These results identify Nab2 as a novel endogenous negative regulator of Egr-1-dependent TGF-b signaling responsible for setting the intensity of fibrotic responses. Defective Nab2 expression or function in dermal fibroblasts might play a role in persistent fibrotic responses in scleroderma. Citation: Bhattacharyya S, Wei J, Melichian DS, Milbrandt J, Takehara K, et al. (2008) The Transcriptional Cofactor Nab2 Is Induced by TGF-b and Suppresses Fibroblast Activation: Physiological Roles and Impaired Expression in Scleroderma. PLoS ONE 4(10): e7620. doi:10.1371/journal.pone.0007620 Editor: Christophe Egles, Tufts University, United States of America Received June 11, 2009; Accepted October 1, 2009; Published October 26, 2009 Copyright: 2008 Bhattacharyya et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This study is supported by grants from the National Institutes of Health (AR-04239), Department of Defense (DOD PR054101), and the Scleroderma Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: [email protected]