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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：
9187438
负责人：
Erin Eun-Young Ahn
金额：
$ 34.66万
依托单位：
UNIVERSITY OF SOUTH ALABAMA
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 2020-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9187438
关键词：
Affect Binding Biological Biological Assay Blood Cells Cell Cycle Cell Maintenance Cell Proliferation Cells 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 Gene Targeting 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 Recruitment Activity Repression Research Role Stem cells Testing Transcriptional Regulation Transplantation Untranslated RNA Up-Regulation base epigenetic regulation gene repression genome-wide 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 self-renewal 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.