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SON-mediated gene expression and leukemia

SON介导的基因表达和白血病

基本信息

批准号：
9828073
负责人：
Erin Eun-Young Ahn
金额：
$ 33.97万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-12-01 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9828073
关键词：
Affect Binding Biological Biological Assay Blood Cells Cell Cycle Cell Maintenance Cell Proliferation Cells Cellular Assay ChIP-seq Child Chromatin Complex DNA DNA Binding DNA Repair DNA-Binding Proteins Data Development Disease Dominant-Negative Mutation Epigenetic Process Exhibits Gene Activation Gene Expression Genes Genetic Transcription Genomics Goals Hematopoiesis Hematopoietic Neoplasms Hematopoietic stem cells Histone H3 Human Investigation Knowledge Length Leukemic Cell Location Lysine MALAT1 gene Maintenance Malignant Neoplasms Mediating Mediator of activation protein Methylation Modification Molecular Mus Mutation Nuclear Protein Patients Protein Isoforms RNA RNA Binding RNA Splicing RNA-Binding Proteins Reagent Repression Research Role Testing Transcriptional Regulation Transplantation Untranslated RNA Up-Regulation base epigenetic regulation gene repression genome-wide hematopoietic differentiation hematopoietic stem cell self-renewal histone modification human embryonic stem cell in vivo insight knock-down leukemia leukemogenesis mortality mouse model new therapeutic target novel overexpression pluripotency promoter public health relevance recruit self-renewal stem cells stemness therapeutic target transcription factor young adult

项目摘要

DESCRIPTION (provided by applicant): Leukemia is the most common and devastating cancer affecting children and young adults with high mortality rate. Mutations and altered expression of numerous transcription factors, RNA splicing factors and epigenetic modifiers have been identified in leukemia patients, indicating that dysregulation of gene expression machinery is a hallmark of leukemia. SON is a poorly characterized nuclear protein highly expressed in blood cells, and the critical role of SON in RNA splicing of cell cycle- and pluripotency-related genes was recently identified. Besides its RNA-binding ability and the function as a splicing mediator, SON has also been shown to repress transcription of a few mammalian genes. However, the mechanisms of SON-mediated transcriptional regulation and the disease relevance of SON functions are largely unknown. Our preliminary data from SON ChIP-seq analyses revealed that SON interacts with multiple genomic locations to suppress transcription of target genes which include critical factors associated with hematopoiesis, stem cell maintenance and leukemogenesis. Interestingly, SON knockdown results in increased tri-methylation of lysine 4 on histone H3 (H3K4me3), eliciting gene activation at SON-targeted promoters. We also found that the C-terminus of SON containing RNA-binding motifs is necessary to suppress promoter activity, and identified several candidates of SON-interacting non-coding RNAs. More interestingly, SON E, a short SON isoform lacking RNA-binding motifs, is highly expressed in leukemia. In addition, SON E exhibits a dominant negative effect on full-length SON function in transcriptional repression, while enhancing full-length SON-mediated RNA splicing. Based on our preliminary data, we hypothesize that the SON complex containing RNA components suppresses target gene activation through regulating histone modifications, and upregulation of SON E (a short isoform) causes alterations in SON target gene expression and enhances hematopoietic stem cell self-renewal, which facilitates leukemogenesis. To test this hypothesis, we propose following specific aims; (1) To elucidate the molecular mechanisms of SON-mediated transcriptional repression. (2) To investigate the effect of SON E upregulation on gene expression, proliferation and self-renewal in hematopoietic stem cells. (3) To identify the role of SON E in leukemogenesis. Investigation of the function of SON and its short isoform in controlling gene expression and leukemogenesis will generate valuable mechanistic insights into a novel mode of fine-tuning of gene expression, and reveal new therapeutic targets for leukemia and other hematopoietic malignancies.

描述（由申请人提供）：白血病是影响儿童和年轻人的最常见、最具破坏性的癌症，死亡率很高。在白血病患者中发现了多种转录因子、RNA剪接因子和表观遗传修饰因子的突变和表达改变，表明基因表达机制失调是白血病的一个标志。 SON 是一种在血细胞中高度表达的核蛋白，其特征尚不清楚，最近发现 SON 在细胞周期和多能性相关基因的 RNA 剪接中的关键作用。除了其 RNA 结合能力和剪接介体的功能外，SON 还被证明可以抑制一些哺乳动物基因的转录。然而，SON 介导的转录调控机制以及 SON 功能与疾病的相关性在很大程度上尚不清楚。我们来自 SON ChIP-seq 分析的初步数据显示，SON 与多个基因组位置相互作用，抑制靶基因的转录，其中包括与造血、干细胞维持和白血病发生相关的关键因子。有趣的是，SON 敲低会导致组蛋白 H3 (H3K4me3) 上赖氨酸 4 的三甲基化增加，从而引发 SON 靶向启动子的基因激活。我们还发现 SON 的 C 末端含有 RNA 结合基序对于抑制启动子活性是必要的，并鉴定了几种 SON 相互作用的非编码 RNA 候选者。更有趣的是，SON E（一种缺乏 RNA 结合基序的短 SON 亚型）在白血病中高度表达。此外，SON E 在转录抑制中对全长 SON 功能表现出显性负效应，同时增强全长 SON 介导的 RNA 剪接。根据我们的初步数据，我们假设含有RNA成分的SON复合物通过调节组蛋白修饰来抑制靶基因激活，而SON E（一种短亚型）的上调会导致SON靶基因表达的改变并增强造血干细胞的自我更新，从而促进白血病的发生。为了检验这一假设，我们提出以下具体目标； (1)阐明SON介导的转录抑制的分子机制。 (2)探讨SON E上调对造血干细胞基因表达、增殖和自我更新的影响。 (3)确定SON E在白血病发生中的作用。对SON及其短亚型在控制基因表达和白血病发生中的功能的研究将为基因表达微调的新模式产生有价值的机制见解，并揭示白血病和其他造血系统恶性肿瘤的新治疗靶点。

项目成果

期刊论文数量（17）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

SON and Its Alternatively Spliced Isoforms Control MLL Complex-Mediated H3K4me3 and Transcription of Leukemia-Associated Genes.

DOI：
10.1016/j.molcel.2016.02.024
发表时间：
2016-03-17
期刊：
Molecular cell
影响因子：
16
作者：
Kim JH;Baddoo MC;Park EY;Stone JK;Park H;Butler TW;Huang G;Yan X;Pauli-Behn F;Myers RM;Tan M;Flemington EK;Lim ST;Ahn EY
通讯作者：
Ahn EY

Nuclear focal adhesion kinase induces APC/C activator protein CDH1-mediated cyclin-dependent kinase 4/6 degradation and inhibits melanoma proliferation.

DOI：
10.1016/j.jbc.2022.102013
发表时间：
2022-06
期刊：
JOURNAL OF BIOLOGICAL CHEMISTRY
影响因子：
4.8
作者：
Murphy, James M.;Jeong, Kyuho;Ahn, Eun-Young Erin;Lim, Ssang-Taek Steve
通讯作者：
Lim, Ssang-Taek Steve

FAK Activation Promotes SMC Dedifferentiation via Increased DNA Methylation in Contractile Genes.

DOI：
10.1161/circresaha.121.319066
发表时间：
2021-12-03
期刊：
Circulation research
影响因子：
20.1
作者：
Jeong K;Murphy JM;Kim JH;Campbell PM;Park H;Rodriguez YAR;Choi CS;Kim JS;Park S;Kim HJ;Scammell JG;Weber DS;Honkanen RE;Schlaepfer DD;Ahn EE;Lim SS
通讯作者：
Lim SS

miR-125b regulates differentiation and metabolic reprogramming of T cell acute lymphoblastic leukemia by directly targeting A20.