title: Tetramethylpyrazine promotes SH-SY5Y cell differentiation into neurons through epigenetic regulation of Topoisomerase IIβ.
abstract: Tetramethylpyrazine (TMP) is an active compound extracted from the traditional Chinese medicinal herb Chuanxiong. Recently, it has been reported that TMP enhances neurogenesis, and promotes neural stem cell differentiation toward neurons. However, its molecular basis remains unknown. Topoisomerase IIβ (TopoIIβ) is a nuclear enzyme with an essential role in neuronal development. This study aimed to investigate whether TopoIIβ is involved in TMP-induced neuronal differentiation. We examined the effect of TMP on neuronal differentiation of SH-SY5Y cells. It was found that TMP inhibited cell proliferation and induced G0/G1 cell cycle arrest. TMP promoted SH-SY5Y cells to differentiate toward post-mitotic neurons characterized by long, out-branched neurites and up-regulated neuronal markers, microtubule-associated protein 2 (MAP2) and tau. Meanwhile, we demonstrated that TopoIIβ was highly expressed following TMP treatment. To unravel how TMP affects TopoIIβ expression, two chromatin active markers, acetylated histone H3 (Ac-H3) and acetylated histone H4 (Ac-H4) were examined in this study. Our data showed that the levels of Ac-H3 and Ac-H4 were positively correlated with TopoIIβ expression in the processes of neuronal differentiation. We further performed chromatin immunoprecipitation (ChIP) analysis and identified that TMP enhanced the recruitment of Ac-H3 and Ac-H4 to the TopoIIβ gene promoter region. Therefore, we concluded that TMP may stimulate neuronal differentiation of SH-SY5Y cells through epigenetic regulation of TopoIIβ. These results suggest a novel molecular mechanism underlying TMP-promoted neuronal differentiation.
authors.affiliation: Cell Biology Division, Institute of Basic Medicine, Hebei Medical University, Hebei, PR China.
authors.forename: Y
authors.initials: Y
authors.lastname: Yan
authors.affiliation: Cell Biology Division, Institute of Basic Medicine, Hebei Medical University, Hebei, PR China.
authors.forename: J
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Department of Human Anatomy, Hebei Medical University, Hebei, PR China.
authors.forename: C
authors.initials: C
authors.lastname: Cao
authors.affiliation: Cell Biology Division, Institute of Basic Medicine, Hebei Medical University, Hebei, PR China.
authors.forename: Z
authors.initials: Z
authors.lastname: Jia
authors.affiliation: Cell Biology Division, Institute of Basic Medicine, Hebei Medical University, Hebei, PR China.
authors.forename: N
authors.initials: N
authors.lastname: Zhou
authors.affiliation: Department of Human Anatomy, Hebei Medical University, Hebei, PR China.
authors.forename: S
authors.initials: S
authors.lastname: Han
authors.affiliation: Cell Biology Division, Institute of Basic Medicine, Hebei Medical University, Hebei, PR China.
authors.forename: Y
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Cell Biology Division, Institute of Basic Medicine, Hebei Medical University, Hebei, PR China.
authors.forename: Y
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Cell Biology Division, Institute of Basic Medicine, Hebei Medical University, Hebei, PR China.
authors.forename: J
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Cell Biology Division, Institute of Basic Medicine, Hebei Medical University, Hebei, PR China. Electronic address: yanyunli2015@163.com.
authors.forename: Y
authors.initials: Y
authors.lastname: Yan
authors.affiliation: Department of Human Anatomy, Hebei Medical University, Hebei, PR China; Hebei Key Laboratory for Brain Aging and Cognitive Neuroscience, Hebei, PR China.
authors.forename: H
authors.initials: H
authors.lastname: Cui
mesh_terms: D000107:Acetylation; D002454:Cell Differentiation / Q000187:drug effects* / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004250:DNA Topoisomerases, Type II / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D044127:Epigenesis, Genetic / Q000187:drug effects*; D006657:Histones / Q000378:metabolism; D006801:Humans; D016501:Neurites / Q000187:drug effects / Q000378:metabolism; D009447:Neuroblastoma; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D011719:Pyrazines / Q000494:pharmacology*
chemical_list: D004268:DNA-Binding Proteins; D006657:Histones; D011719:Pyrazines; D004250:DNA Topoisomerases, Type II; C017953:tetramethylpyrazine
keywords: SH-SY5Y cell; Topoisomerase IIβ; histone acetylation; neurite outgrowth; neuronal differentiation; tetramethylpyrazine