人间充质干细胞成骨分化早期HOX家族3’端基因转录的表观遗传调控
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摘要
间充质干细胞(mesenchymal stem cells MSCs)是一类具有多分化潜能的成体干细胞,在体内外可以被人工定向诱导分化成多种不同的细胞。有报道表明在干细胞分化的过程中,细胞核内染色质发生改构。HOX家族基因作为一类转录因子,在胚胎发育以及细胞分化过程中发挥着十分重要作用。本文通过体外定向诱导骨髓间充质干细胞向成骨细胞分化,对比分化前后细胞中HOX家族基因的表达状况,发现HOX家族3’端基因的表达水平在MSCs成骨分化早期是降低的。而通过进一步研究发现,HOX家族3’端基因启动子区的组蛋白H3-Lys9乙酰化下降和二甲基化上升。一系列实验证据表明,在间充质干细胞的成骨分化过程中,HOX家族3’端基因表达受到抑制,而这种抑制作用与其启动子区发生的染色质重塑事件密切相关。
Mesenchymal stem cells (MSCs) are stromal cells that can be derived from several tissues, such as bone marrow and placenta. They can differentiate into several cell lineages including osteoblasts, chondrocytes, adipocytes and myoblasts in vivo and in vitro. It has been reported that the mammalian chromatin undergoes global remodeling during early development. HOX family encoding the class of transcription factors called homeobox, which is spatially and temporally regulated during embryonic development. We induced MSCs differentiated into osteoblasts,and investigated the expression of the genes in HOX family during the osteogenetic process. We found that the genes in 3’side of HOX family were down-regulated in the early stage of MSCs osteogenetic differentiation, whereas acetylation of H3-lys9 was declined and H3-lys9 methyation was raised in their promoter regions. Our data indicated that the 3’side genes in HOX family are repressed in the process of MSCs differentiated into osteoblasts, and the inhibition is closely linking with the chromatin remodeling.
Mesenchymal stem cells (MSCs) are stromal cells that can be derived from several tissues, such as bone marrow and placenta. They can differentiate into several cell lineages including osteoblasts, chondrocytes, adipocytes and myoblasts in vivo and in vitro. It has been reported that the mammalian chromatin undergoes global remodeling during early development. HOX family encoding the class of transcription factors called homeobox, which is spatially and temporally regulated during embryonic development. We induced MSCs differentiated into osteoblasts,and investigated the expression of the genes in HOX family during the osteogenetic process. We found that the genes in 3’side of HOX family were down-regulated in the early stage of MSCs osteogenetic differentiation, whereas acetylation of H3-lys9 was declined and H3-lys9 methyation was raised in their promoter regions. Our data indicated that the 3’side genes in HOX family are repressed in the process of MSCs differentiated into osteoblasts, and the inhibition is closely linking with the chromatin remodeling.
引文
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[19] Cosma M P, Tanaka T, Nasmyth K. Ordered recruitment of transcription and chromatin remodeling factors to a cell cycle- and developmentally regulated promoter [J]. Cell, 1999, 97: 299-311.
[20] Grozinger CM, Chao ED, Blackwell HE, et al. Identification of a class of small molecule inhibitors of the Sirtuin family of NAD-dependent deacetylases by phenotypic screening [J]. J Biol Chem, 2001, 276: 38837–38843.
[21] Spotswood HT, Turner BM. An increasingly complex code [J]. J Clin Invest, 2002, 110: 577–582.
[22] Tsai S C, Seto E. Regulation of histone deacetylase-2 by protein kinase CK2 [J]. J Biol Chem, 2002, 277 (35): 31826-31833.
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[34] Tachibana M, Ueda J, Fukuda M, et al. Histone methyltransferases G9a and GLP form heteromeric complexes and are both crucial for methylation of euchromatin at H3-K9 [J]. Genes Dev, 2005, 19: 815-826.
[35] Tachibana M, Sugimoto K, Nozaki M, et al. G9a histone methylaansferase plays a dominant role in euchromatic histone H3 lysine 9 methylation and is essential for early embryogenesis [J]. Genes Dev, 2002, 16: 1779-1791.
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[37] Elgin SCR, Grewal SIS. Heterochromatin: silence is golden [J]. Curr. Bio1, 2003, 13: R895-898.
[38] Partridge JF, Borgstrom B, Allshire RC. Distinct protein interaction domains and protein spreading in a complex centromere [J]. Genes Dev, 2000, 14: 783-791.
[39] Partridge JF, Scot KS, Bannister AJ, et al. Cis-acting DNA from fission yeast centromeres mediates histone H3 methylation and recruitment of silencing factors and cohesin to an ectopic site [J]. Cutr Biol, 2002, 12: 1652-1660.
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[41] Sugiyama T, Cam H, Verdel A, et al. RNA-dependent RNA polymerase is an essential component of a self-enforcing loop coupling heterochromatin assembly to siRNA production [J]. Proc. Natl Acad. Sci, 2005, 102: 152-157.
[42] Paik WK, Kim S. Enzymatic demethylation of calf thymus histones [J]. Biochem. Biophys. Res. Commun, 1973, 51:7 81-788.
[43] Shi Y, Lan F, Matson C, et al. Histone demethylation mediated by the nuclear amine oxidase homolog LSD1 [J]. Cell, 2004, 119: 941-953.
[44] Reyes M, Lund T, Lenvik T, et al. Purification and ex vivo expansion of postnatal human marrow mesodermal progenitor cells [J]. Blood, 2001, 98 (9): 2615-2625
[45] Frankel MS. In search of stem cell policy [J]. Science, 2000, 287: 1397
[46] Monticone M, Liu Y, Tonachini L, et al. Gene expression profile of human bone marrow stomal cells determined by restriction fragment differential display analysis [J]. Journal of Cellular Biochemistry, 2004, 92: 733–744
[47] Baksh D, Song L, Tuan RS, et al. Adult mesenchymal stem cells: characterization, differentiation, and application in cell and gene therapy [J]. J Cell Mol Med, 2004, 8 (3):301-316
[48] 王运涛.骨髓间充质干细胞分离培养的研究进展 [J]. 国外医学生物工程分册,2002, 25 (4): 184.
[49] Hgushi H, Caplan AI. Stem cell technology and biocramics. From cel to gene engineering [J]. J Biomed Mater Res, 1999, 48 (6): 913.
[50] Conget PA, Minguel JJ. Phenotypical and functional properties of human bone marrow mesenchymal progenitor cells [J]. J Cell Physiol, 1999, 181 (1): 67.
[51] Bellows CG, Ciaccia A, Heersche JN. Osteoprogenitor cells in cell populations derived from mouse and rat calvaria differ in their response to corticosterone, cortisol, and cortisone [J]. Bone, 1998, 23: 119-125
[52] Pittenger MF, Mackay AM, Beck SC, et al. Multolineage potential of adult human mesenchymal stem cells [J]. Science, 1999, 284 (2): 143.
[53] Bruder SP, Jaiswal N, Haynesworth SE. Growth kinetics, self-renewal, and the osteogential of purified human mesenchymal stem cells during extensive subculativtion and following cryopreservation [J].J Cell Biochem, 1997, 64 (2): 278.
[54] Ferrari G, Coletta M, Paolucci E, et al. Muscle regeneration by bone marrow-derived myogenic progenitors [J].Science, 1998, 279: 1528.
[55] Brazerlton TR, Rossi FM V, Keshet GI, et al. From marrow to brain: expression of neuronal phenotypers in adult mice [J].Science, 2000, 290 (5497): 1775.
[56] Rockop DL. Marrow stromal cells as stem cells for non-hematopoietic tissues [J]. Science, 1997, 276 (5309): 71-74.
[57] Sanchez-Ramos J, Song S, Cardozo-pelaze F, et al. Adult bon marrow stromal cells differentiate into neural cells in vitro [J]. Exp Neuro1, 2000, 164 (2): 247.
[58] Nuttall ME, Patton, Olives DL, et al. Human trabecular bone cells are able to express both osteoblastic and adipocytic phenotype: implications for osteogenic disorders [J].J Bone Miner Res, 1998, 13 (3): 371.
[59] Leek, Majumdav Mk, Buyaner D, et al. Human mesenchymal stem cels maintain transgene expression during expansion and differentiation [J]. Mol Ther, 2001, 3 (6): 857.
[60] Dao MA, Nolta JA. Use of the nx/hu reenograft modle of human hematopoiesis to optimiz methods for retroviral mediated stem cell transduction [J]. Int J Mol Med, 1998, 1: 257.
[61] Lazarus HM, Haynesworth SE, Gerson SL, et al. Ex vivo expansion and subsequent infusion of human bine marrow-derived stromal progenitor cels (mesenchymal progenitor cells); implication for therapeutic use[J]. Bone Transplant, 1998, 16: 557.
[62] Pereira RF, O Hara MD, Laptev AV, et al. Marrow stromal cells as a source of progenitor cells for non一hematopoictic tissues in transgeneic mice with a phenotype of osteogenesis imperfecta [J]. Proc Acad Sci USA, 1998, 95: 1142.
[63] Boudreal N, Catherine, Andrews, et al. Induction of the angiogenic phenotype by HoxD3 [J]. J Cell Biol, 1997, 139(1): 257-264.
[64] Osborne J, Hu C, Hawley C, et al. Expression of HoxD10 gene in normal and endometrial adenocarcinoma [J]. J Soc Gynecol Invest, 1998, 5(3): 277-280.
[65] Borrow J, Shearman AM, Stanton VP. The t (7, 11) (p15, p15) translation in acute myeolid leukemia fuses the genes for mucleopolin NUP98 and class I homeoprotein HoxA9 [J]. Nature Genetic, 1996, 12(2): 159-167.
[66] Nishiyama M, Arai Y, Tsunematsu Y, et al. 11p15 translocations involving the NUP98 gene in childhood therapy-related acute myeloid leukemia / myelodysplastic syndrome [J]. Genes Chromosom Cancer, 1999, 26(3): 215-220.
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