Function Of Hi Stone Methyltransferases MLL1and SETD2in The Regulation Of Cell Signaling

Histone post-translational modifications, the important part of epigenetics, play essential roles in the structure and function of chromatin. In1964, Allfrey discovered the histone acetylation and methylation. Since then, a wide variety of histone modifications have been discovered including but not limited to phosphorylation, ubiquitination, sumoylation, ADP-ribosylation, deiminationand proline isomerization. Since histone modifications regulate the protein binding sites, charge, structure and stability of chromatin, they directly function in diverse biological processes such as DNA replication, transcription regulation, DNA damage response, DNA repair, heterochromatin maintenance. DNA recombination and gene imprinting, to sustain biological activities of cells.Histone methylation correlates tightly with transcription regulation. Histone methylation typically occurs at lysine or arginine residues. Up to now, methylation sites mainly distribute in histone H3and H4. Among these, methylation of histone H3K4and H3K36, mainly enrich on actively transcribed genes.Tri-methylation of histone H3K4, which is restricted to the promoter regions of actively transcribed genes, functions in both basal and induced transcription activation by recruiting activatiors such as histone acetyltransferases and general transcription factors. MLL family consists of key enzymes catalyzing the methylation of H3K4in mammalian, including MLL1, MLL2, MLL3, MLL4, SETD1A and SETD1B. By interacting with multiple nuclear regulatory proteins and controlling gene transcript ional activity, MLL family members participate in both basal and induced transcription. They are essential for multiple biological processes including embryo genes is, differentiation, signal transduction, cell cycle, DNA damage and repair.Tri-methylation of histone H3K36, restricted to the gene bodies of actively transcribed genes, functions in mRNA alternative splicing and DNA mismatch repair by recruiting splicing factors and mismatch repair protein respectively. Histone methyltransferase SETD2, regarded as the major methyltransferase of H3K36trimethylation in mammals, is recruited to chromatin by Ser2phosphorylated C-terminal domain (CTD) of pol ?. H3K36me3acts as a docking site for splicing factor MRG15and influences the splicing decision. In DNA mismatch repair, SETD2-mediated H3K36me3around the damage sites recruits the mismatch recognition proteins.In signaling transduction, cells need to respond rapidly to extracellular stimulus and translate the signal into a specific transcriptional state. At the same time, signal transduction pathways can be used as model systems for the study of induced transcription. Signaling transduction can be separated into two parts, extranuclear and intranuclear signaling. During the extranuclear signaling, receptors transform the signals into cellular cascades and usually activate a specific factor. Then the activated factor enters the nuclear and changes the transcriptional activity of target genes, which is defined as intranuclear signaling, including chromatin remodeling, histone modification and regulator recruitment.Here we studied the function of histone methyltransferases in several signaling transduction pathways. Firstly, we found that MLL1is required for the full activation of NF-kB signaling downstream genes. MLL1interacts with p65. The cytoplasmic MLL1translocates into the nuclear and promotes induced gene expression in response to TNFa by targeting to and catalyzing the H3K4me3modification on the promoters of a subset ofNF-KB target genes. Moreover, we proved that other MLL family members including MLL2, SETD1A, SETD1B are involved in the activation of NF-KB target genes, which exhibit compensation and difference regulation pattern to MLL1. Secondly, we found MLL1is involved in the cell response to tunicamycin-induced ER stress. The deficiency of MLL1affects the extranuclear signaling of endoplasmic reticulum stress response. Further studies indicate that MLL1binds to and catalyzes H3K4me3on promoters of H6pd, a regulator critical for protein glycosylation. By controlling its expression, MLL1is involved in the activation of UPR pathway and ER homeostasis. Thirdly, we found that SETD2represses the tumorgenesis of several cancer cell lines and regulates the tumor-associated cell signaling pathways such as p53and hypoxia stress signaling.In conclusion, our work revealed that histone methyltransferases indeed participate in cell signaling and exhibit spatiotemporal, diverse and complicated regulatory mechanisms. Multi-stage regulatory exists at both extranuclear and intranuclear levels. Histone methyltransferases regulate gene transcription by directly targeting the histone modifications on downstream genes, as well as regulating the signaling modulators. Our results presented examples that histone modifications mediate signaling pathways, and provided theoretical basis for the future studies about the epigenetic mechanisms of signaling transduction.