Short biologically active peptides as epigenetic modulators of gene activity

Abstract

Short (2–4 aa) peptides investigated increased life span of rats and improved various physiological functions and health status in aged people. Biological activities of peptides are tissue (cell) specific. Peptide bronchogen AlaGluAspLeu (AEDL) regulates synthesis of the Ki67, Mcl-1, p53, CD79, and NOS-3 proteins in cultures of the human bronchoepithelial cells. Bronchogen activates the expression of genes coding for the bronchoepithelial cell differentiation factors Nkx2.1, SCGB1A1, SCGB3A2, FoxA1, FoxA2, as well as MUC4, MUC5AС, and SftpA. Pancragen LysGluAspTrp (KEDW) increases expression of many differentiation factor genes in human pancreatic cell culture. The regulatory peptide actions seem to be due mainly to site-specific peptide–DNA binding. Peptides are able to penetrate into the animal cell, nucleus, and nucleolus; therefore, in principle, they may interact potentially with various components of the cytoplasm and nucleus including DNA and RNA. In vitro peptides interact with various oligonucleotides and DNA; they can discriminate between methylated and unmethylated DNAs. Peptides investigated interact with histone H1 and core histones; this interaction depends on the histone nature and peptide primary structures. Peptides modulate specifically the in vitro action of eukaryotic CNG-sitespecific endonucleases. It is suggested that binding of peptides to gene promoters that seems to protect promoter against methylation may be a mechanism of regulation of transcription by peptides. It was shown that in vivo peptides can influence methylation of gene promoters, and, in fact, the modulation of gene activity by peptides is associated often with diminution of CpG methylation in respective gene promoters. Thus, the site-specific (complementary) interactions of short biologically active peptides with DNA may control epigenetically the cell genetic functions, and these interactions seem to play an important role in regulation of gene activity even at the earliest stages of life origin and in the evolution. Besides, the site-specific interactions of peptides with histone tails in chromatin may serve as other control epigenetic mechanisms of regulation of gene activity and cell differentiation.