Abstract
PLOD2 (procollagen-lysine, 2-oxoglutarate 5-dioxygenase 2) hydroxylates lysine residues in collagen telopeptides and is essential for collagen pyridinoline cross-link formation. PLOD2 expression and subsequent pyridinoline cross-links are increased in fibrotic pathologies by transforming growth factor β-1 (TGFβ1). In this report we examined the molecular processes underlying TGFβ1-induced PLOD2 expression. We found that binding of the TGFβ1 pathway related transcription factors SMAD3 and SP1-mediated TGFβ1 enhanced PLOD2 expression and could be correlated to an increase of acetylated histone H3 and H4 at the PLOD2 promoter. Interestingly, the classical co-activators of SMAD3 complexes, p300 and CBP, were not responsible for the enhanced H3 and H4 acetylation. Depletion of SMAD3 reduced PLOD2 acetylated H3 and H4, indicating that another as of yet unidentified histone acetyltransferase binds to SMAD3 at PLOD2. Assessing histone methylation marks at the PLOD2 promoter depicted an increase of the active histone mark H3K79me2, a decrease of the repressive H4K20me3 mark, but no role for the generally strong transcription-related modifications: H3K4me3, H3K9me3 and H3K27me3. Collectively, our findings reveal that TGFβ1 induces a SP1- and SMAD3-dependent recruitment of histone modifying enzymes to the PLOD2 promoter other than the currently known TGFβ1 downstream co-activators and epigenetic modifications. This also suggests that additional activation strategies are used downstream of the TGFβ1 pathway, and hence their unraveling could be of great importance to fully understand TGFβ1 activation of genes.
Highlights
procollagen-lysine 2-oxoglutarate 5-dioxygenase 2 (PLOD2) expression and subsequent collagen pyridinoline cross-links are induced in fibrotic tissues by transforming growth factor -1 (TGF1)
TGF1-induced PLOD2 Expression Depends on activin receptorlike kinase 5 (ALK5) and Proximal Promoter Activation—To confirm that PLOD2 expression is enhanced by TGF1 in our skin fibroblasts, we performed Western blot staining
PLOD2 is considered a fibrotic marker since its expression and the resulting pyridinoline cross-links are increased in various scarred tissues and in vitro in fibroblast by profibrotic cytokines such as TGF1 (4, 5, 38, 43, 44)
Summary
PLOD2 expression and subsequent collagen pyridinoline cross-links are induced in fibrotic tissues by TGF1. We found that binding of the TGF1 pathway related transcription factors SMAD3 and SP1-mediated TGF1 enhanced PLOD2 expression and could be correlated to an increase of acetylated histone H3 and H4 at the PLOD2 promoter. Our findings reveal that TGF1 induces a SP1- and SMAD3-dependent recruitment of histone modifying enzymes to the PLOD2 promoter other than the currently known TGF1 downstream co-activators and epigenetic modifications. This suggests that additional activation strategies are used downstream of the TGF1 pathway, and their unraveling could be of great importance to fully understand TGF1 activation of genes
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