title: G9a inhibition promotes neuronal differentiation of human bone marrow mesenchymal stem cells through the transcriptional induction of RE-1 containing neuronal specific genes.
abstract: Recent studies have shown that epigenomic modifications are significantly associated with neuronal differentiation. Many neuronal specific genes contain the repressor element-1 (RE-1), which recruits epigenetic modulators, such as the histone methyltransferase G9a and interrupts the expression of neuronal genes in non-neuronal cells. This study investigated the functional role of G9a during neuronal differentiation of human bone marrow mesenchymal stem cells (BM-MSCs). Human BM-MSCs treated with the G9a inhibitor BIX01294 showed an increased expression of various neuronal-lineage genes. Using genomic sequence analysis, we identified RE-1 consensus sequences in the proximal region of several neuronal-specific genes. Chromatin immunoprecipitation (ChIP) assay results have showed that H3K9me2 (dimethylation of lysine 9 on histone 3) occupancy at RE-1-containing sequences from neuronal-specific genes was significantly decreased in BIX01294-MSCs. When BIX01294-MSCs were differentiated with neuronal induction medium, cells differentiated more effectively into neuron-like cells, complete with a cell body and dendrites. Expression of neuronal-specific genes containing the RE-1 sequences was significantly increased in differentiated BIX01294-MSCs, as confirmed by immunocytochemical staining and immunoblotting. Thus, this study shows that BIX01294 pretreated human BM-MSCs can be effectively differentiated into neuron-like cells by induced expression of neuronal-specific genes containing RE-1 sequences.
authors.affiliation: Department of Biology, College of Natural Science, Chosun University, Gwangju 501-759, Republic of Korea; Department of Life Science, BK21-Plus Research Team for Bioactive Control Technology, Chosun University, Gwangju 501-759, Republic of Korea.
authors.forename: Ho-Tae
authors.initials: HT
authors.lastname: Kim
authors.affiliation: Department of Biology, College of Natural Science, Chosun University, Gwangju 501-759, Republic of Korea; Department of Life Science, BK21-Plus Research Team for Bioactive Control Technology, Chosun University, Gwangju 501-759, Republic of Korea.
authors.forename: Sin-Gu
authors.initials: SG
authors.lastname: Jeong
authors.affiliation: Department of Biology, College of Natural Science, Chosun University, Gwangju 501-759, Republic of Korea; Department of Life Science, BK21-Plus Research Team for Bioactive Control Technology, Chosun University, Gwangju 501-759, Republic of Korea. Electronic address: gwcho@chosun.ac.kr.
authors.forename: Goang-Won
authors.initials: GW
authors.lastname: Cho
mesh_terms: D001381:Azepines / Q000494:pharmacology; D001854:Bone Marrow Cells / Q000187:drug effects / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D006649:Histocompatibility Antigens / Q000096:biosynthesis*; D011495:Histone-Lysine N-Methyltransferase / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000187:drug effects / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D011799:Quinazolines / Q000494:pharmacology; D012097:Repressor Proteins / Q000096:biosynthesis*; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology; D000099229:RE1-Silencing Transcription Factor
chemical_list: D001381:Azepines; D006649:Histocompatibility Antigens; D011495:Histone-Lysine N-Methyltransferase; D011799:Quinazolines; D012097:Repressor Proteins; D000099229:RE1-Silencing Transcription Factor; C518299:BIX 01294; C445405:EHMT2 protein, human
keywords: BIX01294; Bone marrow mesenchymal stem cells (BM-MSCs); G9a; Neuronal differentiation; RE-1 (repressor element-1); REST (RE-1 silencing transcription factor)