Ghosh Asish K, Vaughan Douglas E
Feinberg Cardiovascular Research Institute, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA.
Front Biosci (Elite Ed). 2012 Jan 1;4(4):1556-70. doi: 10.2741/e480.
Fibrosis is an abnormal fibroblast-activation-associated pathological manifestation in injured organs where excessive non-physiological synthesis and accumulation of extracellular matrix (ECM) proteins by activated/differentiated fibroblasts disrupts tissue homeostasis. Like other eukaryotic genes, expression of ECM protein genes not only depends on its gene sequences in the regulatory region but also influenced by non-genetic factors called epigenetic regulators including acetyltransferases, deacetylases, methyltransferases and microRNAs. The acetyltransferase p300 (ATp300), a transcriptional coactivator, is a major player in the epigenetic regulation of genes whose products are involved in cellular growth, proliferation, apoptosis and essential for embryonic development. ATp300 acetylates specific lysine residues in histones and transcription factors (KAT) and as a transcriptional coactivator it forms a bridge between upstream regulatory element binding protein complex and basal transcriptional machinery. Abnormal coactivator activity-associated diseases are known as coactivator diseases. Abnormalities in ATp300 activities in adults are associated with numerous diseases. Here, we review the significant roles of ATp300 in epigenetic regulation of collagen synthesis and deposition in extracellular spaces, matrix remodeling and tissue fibrogenesis. The present day understanding on the distinct role of acetyltransferases, deacetylases, and deacetylase inhibitors on epigenetic regulation of matrix remodeling and fibrosis has also been discussed.
纤维化是损伤器官中与成纤维细胞异常激活相关的病理表现，在损伤器官中，活化/分化的成纤维细胞过度合成和积累非生理性细胞外基质（ECM）蛋白，破坏了组织稳态。与其他真核基因一样，ECM蛋白基因的表达不仅取决于其调控区域的基因序列，还受到称为表观遗传调节因子的非遗传因素影响，这些因子包括乙酰转移酶、去乙酰化酶、甲基转移酶和微小RNA。乙酰转移酶p300（ATp300）作为一种转录共激活因子，是基因表观遗传调控的主要参与者，其基因产物参与细胞生长、增殖、凋亡，对胚胎发育至关重要。ATp300使组蛋白和转录因子中的特定赖氨酸残基乙酰化（赖氨酸乙酰转移酶），作为转录共激活因子，它在上游调控元件结合蛋白复合体和基础转录机制之间形成桥梁。与共激活因子活性异常相关的疾病被称为共激活因子疾病。成人ATp300活性异常与多种疾病有关。在此，我们综述了ATp300在细胞外空间胶原蛋白合成与沉积、基质重塑和组织纤维化的表观遗传调控中的重要作用。本文还讨论了目前对乙酰转移酶、去乙酰化酶和去乙酰化酶抑制剂在基质重塑和纤维化表观遗传调控中独特作用的认识。
