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Differential biophysical properties of protein condensates formed by a tumor suppressor contribute to sexual dimorphism in cancer

肿瘤抑制因子形成的蛋白质凝聚物的不同生物物理特性导致癌症中的性别二态性

基本信息

批准号：
10173111
负责人：
Hao Jiang
金额：
$ 41.53万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-01 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10173111
关键词：
Affect Alleles Animal Model Back Binding Biochemical Biological Assay Cell model Cells Charge Chimera organism Chromatin Cultured Cells Data Disease Engineering Enhancers Female Foundations Gene Expression Genes Growth Hematologic Neoplasms Homologous Gene Human Immune Impairment Incidence Knowledge Leukemic Cell Link Liquid substance Literature Malignant Neoplasms Mediating Methylation Modeling Molecular Mus Mutagenesis Mutate Mutation Pattern Phase Physical condensation Property Proteins Publications RNA Splicing Regulation Risk Factors Role Sex Bias Testing Therapeutic Transplantation Tumor Suppression Tumor Suppressor Genes Tumor Suppressor Proteins Variant Woman X Chromosome X Inactivation Y Chromosome base biophysical properties cancer genetics follow-up improved in vivo leukemia liquid dynamics male men molecular dynamics novel strategies sexual dimorphism tumor

项目摘要

PROJECT SUMMARY It remains incompletely understood why men are more likely to get and die from cancer than women. Tumor suppressor genes that escape from X-inactivation substantially contribute to the lower cancer incidence in females. Some of these genes, including UTX/KDM6A, have Y- chromosome homologs, but human cancer genetics suggest that the Y homologs are less tumor- suppressive than their X-chromosome counterparts, such that the X-X pairs are more tumor- suppressive than the X-Y homologs. This activity bias contributes to the cancer sex dimorphism, but its underlying molecular mechanisms are unknown. In our preliminary studies, we found that the UTX undergoes liquid-liquid phase separation that is mediated by its core Intrinsically Disordered Region (cIDR), and this property is critical for its tumor suppressive activity by co- condensing MLL4 and its H3K4 mono-methylation activity into the same droplets on chromatin and greatly enhances. We then found that cIDR is the key determinant of the lower tumor suppressive activity of UTY. UTY cIDR has a stronger propensity than UTX cIDR to form condensates, but UTY condensates are less dynamic than UTX condensates. Our results allow us to formulate and further test our central hypothesis that natural variations in the UTX and UTY condensate properties affect their tumor suppressive activity and contribute to male bias in cancer. Specific Aim 1. Determine the contribution of UTY cIDR to its weaker tumor suppressive activity. Specific Aim 2: Link the differential condensate properties to differential tumor suppressive activities through identification of key determinant in UTY cIDR. These studies will lay foundation for follow-up in-depth studies, which will establish a new concept that key and variations related to a fundamental principle of cellular organization contribute to the sexual dimorphisms in cancer incidence.

项目摘要为什么男性比男性更容易患上癌症并死于癌症，妇女从X-失活逃逸的肿瘤抑制基因实质上有助于肿瘤的发生。女性癌症发病率较低。其中一些基因，包括UTX/KDM 6A，具有Y- 染色体同源物，但人类癌症遗传学表明，Y同源物是肿瘤较少，比他们的X染色体对应物更有抑制性，这样X-X对就更有肿瘤- 比X-Y同源物更有抑制性。这种活动偏好导致了癌症的性别二态性，但其潜在的分子机制尚不清楚。在我们的初步研究中，我们发现， UTX经历液-液相分离无序区（cIDR），并且这种性质对于其通过共- 将MLL 4及其H3 K4单甲基化活性浓缩到染色质上的相同液滴中并大大增强。然后我们发现cIDR是下肿瘤的关键决定因素， UTY的抑制活性。UTY cIDR比UTX cIDR更倾向于形成冷凝物，但UTY冷凝物比UTX冷凝物动态性差。我们的结果允许我们制定并进一步测试我们的中心假设，即UTX和UTY的自然变化冷凝物的性质影响它们的肿瘤抑制活性，并有助于在癌具体目标1.确定UTY cIDR对其较弱肿瘤抑制的贡献活动具体目标2：将不同的冷凝物性质与不同的肿瘤联系起来通过鉴定UTY cIDR中的关键决定子来抑制活性。这些研究将为后续的深入研究奠定基础，建立新的概念与细胞组织的基本原则有关的关键和变化有助于癌症发病率中的两性异形。