The epigenetic role of LSD1 in osteoclast differentiation

项目摘要 骨质疏松症和牙周病等疾病每年影响美国数百万人 治疗花费数十亿美元。破骨细胞是大的多核细胞，分泌酸， 蛋白酶来吸收骨。了解调节破骨细胞分化的分子机制 和活性将提供关于过度活跃的破骨细胞如何引起病理性骨丢失的见解， 导致骨质疏松和牙周病。对DNA的可逆修饰，如组蛋白 乙酰化、甲基化、磷酸化和泛素化改变了转录机制， DNA和调节基因表达。赖氨酸特异性脱甲基酶1（LSD 1），也称为KDM 1A，是第一个 经鉴定的能特异性地使组蛋白的单甲基化赖氨酸4和二甲基化赖氨酸4脱甲基的组蛋白脱甲基酶 3（H3 K4 me 1/2）或组蛋白3的赖氨酸9（H3 K9 me 1/2）。LSD 1通过以下方式赋予转录抑制： 使H3 K4去甲基化或通过使H3 K9去甲基化激活转录。LSD 1的机制 调节破骨细胞基因表达和分化的机制目前尚不清楚。初步数据见 这一提议表明LSD 1活性或表达的抑制导致LSD 1单甲基化的增加， H3 K4 me 1和破骨细胞分化的增加。这些初步的数据表明LSD 1是一个阻遏物， 破骨细胞基因表达该建议旨在描述LSD 1在调节破骨细胞中的作用 在动物模型和体外细胞培养模型中（Aim 1）， 受LSD 1调控的破骨细胞基因（Aim 2）。这些研究目标将得到加强， 应用程序的培训目标。这些培训目标包括学习技术，如微型CT，RNA-SEQ 和ChIP-SEQ以及参加期刊俱乐部和地方和国家科学会议。培训 发生在明尼苏达大学，它提供了一个优秀的环境，为研究和 临床牙科培训。

PROJECT SUMMARY Diseases such as osteoporosis and periodontal disease affect millions of individuals annually in the United States and cost billions in treatment. Osteoclasts are large, multinucleated cells that secrete acid and proteases to resorb bone. Understanding the molecular mechanisms that regulate osteoclast differentiation and activity will provide insight as to how the hyper-active osteoclasts causing pathological bone loss, contributes to osteoporosis and periodontal disease. Reversible modifications to DNA such as histone acetylation, methylation, phosphorylation and ubiquitylation alter the access of transcriptional machinery to DNA and regulate gene expression. Lysine-specific demethylase 1 (LSD1), also known as KDM1A, is the first identified histone demethylase capable of specially demethylating mono- and di-methylated lysine 4 of histone 3 (H3K4me1/2) or lysine 9 of histone 3 (H3K9me1/2). LSD1 confers transcriptional repression by demethylating H3K4 or activating transcription by demethylating H3K9. The mechanism by which LSD1 regulates osteoclast gene expression and differentiation is currently unknown. Preliminary data presented in this proposal demonstrate inhibition of LSD1 activity or expression leads to an increase in mono-methylation of H3K4me1 and an increase in osteoclast differentiation. These preliminary data suggest LSD1 is a repressor of osteoclast gene expression. This proposal aims to characterize the role of LSD1 in regulating osteoclast differentiation in both an animal model and as well as in an in vitro cell culture model (Aim 1) and identifying the osteoclast genes that are regulated by LSD1 (Aim 2). These research goals will be enhanced by the training goals of the application. These training goals include learning techniques such as micro-CT, RNA-SEQ and ChIP-SEQ as well as participation in journal clubs and local and national scientific meetings. Training takes place at the University of Minnesota which offers an outstanding environment for both research and clinical dental training.