Defining the role of histone H3K4 mono-methyltransferase dysfunction in urothelial carcinoma

定义组蛋白 H3K4 单甲基转移酶功能障碍在尿路上皮癌中的作用

基本信息

  • 批准号:
    10522552
  • 负责人:
  • 金额:
    $ 60.23万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2022
  • 资助国家:
    美国
  • 起止时间:
    2022-09-01 至 2027-08-31
  • 项目状态:
    未结题

项目摘要

Project Summary/Abstract Urothelial carcinoma (UC) involves the urothelial cells that line the bladder, kidney and ureters and is a major cause of morbidity and mortality in the US, especially in men. Bladder UC can be clinically separated into nonmuscle invasive (NMIBC) and muscle invasive (MIBC). MIBC accounts for the vast majority of metastasis and mortality, having only a ~50% cure rate. Patients with treated NMIBC are at risk of recurrence or progression to MIBC at prior or de novo sites. Over half of urothelial cancer, regardless of site of origin, harbor loss of function mutations in the histone demethylase KDM6A (UTX) and in two highly homologous histone methyltransferases KMT2C (MLL3) and KMT2D (MLL4). These proteins form the MLL3/4-COMPASS (COMplex of Proteins ASsociated with Set1)-like complex that regulate enhancer function, partly through methylation of histones at enhancers. Enhancers are regions of DNA that regulate lineage specific transcriptional programs. Recent studies have shown that patients with two urothelial carcinomas in far away sites (ureter and bladder) harbor the same COMPASS-like mutation. Further sequencing of histologically benign urothelium identify frequent mutations in the complex at expand over time. Our hypothesis is that these mutations under “field-cancerization” of the urothelium. Our lab has generated a genetically engineered mouse model with deletion of Kmt2c, Kmt2d, or the combination in the urothelium. The urothelium of these mice exhibit no histologic abnormalities. However, transcriptome analysis shows the urothelium exhibit increased stemness and functional studies show they exhibit increased organoid forming abilities. When crossed into the Pten conditional deletion mouse, there was robust cooperativity in tumorigenesis. The overall objective of this proposal is to utilize our recently generated mouse models of urothelial this COMPASS-like complex loss to mechanistically understand its role in tumor urothelial suppression. Specifically, in Aim 1, we seek to determine the stemness, clonal dynamics, oncogene and carcinogen susceptibility of urothelium harboring mutations in this COMPASS-like complex, using lineage tracing, organoid culture, and single-cell RNA-sequencing. In Aim 2, we seek to determine the functional interplay between MLL3/4-COMPASS dysfunction and oncogene activation. In Aim 3, we will seek to define how loss of Kmt2c and Kmt2d in urothelial cells affect enhancer and promoter function. Active enhancers are genomic regions of open chromatin with transcription factor binding, divergent transcription of enhancer RNA, and looping to promoters. We will study each step by global mapping of histone marks, chromatin accessibility, mRNA transcription of associated gene and looping to promoters using state-of the art epigenetics techniques.
项目总结/文摘

项目成果

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Yu Chen其他文献

Yu Chen的其他文献

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{{ truncateString('Yu Chen', 18)}}的其他基金

Automatic Wide-Field Optical Coherence Tomography for Assessment of Transplant Kidney Viability
用于评估移植肾活力的自动广域光学相干断层扫描
  • 批准号:
    10501992
  • 财政年份:
    2022
  • 资助金额:
    $ 60.23万
  • 项目类别:
Iodine Catalyzed Cross-Coupling Reactions
碘催化的交叉偶联反应
  • 批准号:
    10333396
  • 财政年份:
    2022
  • 资助金额:
    $ 60.23万
  • 项目类别:
Iodine Catalyzed Cross-Coupling Reactions
碘催化的交叉偶联反应
  • 批准号:
    10643819
  • 财政年份:
    2022
  • 资助金额:
    $ 60.23万
  • 项目类别:
Evolution and inhibition of carbapenemase in beta-lactam resistance
β-内酰胺耐药中碳青霉烯酶的进化和抑制
  • 批准号:
    10598501
  • 财政年份:
    2021
  • 资助金额:
    $ 60.23万
  • 项目类别:
Evolution and inhibition of carbapenemase in beta-lactam resistance
β-内酰胺耐药中碳青霉烯酶的进化和抑制
  • 批准号:
    10385772
  • 财政年份:
    2021
  • 资助金额:
    $ 60.23万
  • 项目类别:
Patient-Derived Models of Prostate Cancer for Personalized Medicine
用于个体化医疗的前列腺癌患者衍生模型
  • 批准号:
    10472536
  • 财政年份:
    2019
  • 资助金额:
    $ 60.23万
  • 项目类别:
Patient-Derived Models of Prostate Cancer for Personalized Medicine
用于个体化医疗的前列腺癌患者衍生模型
  • 批准号:
    10219178
  • 财政年份:
    2019
  • 资助金额:
    $ 60.23万
  • 项目类别:
Patient-Derived Models of Prostate Cancer for Personalized Medicine
用于个体化医疗的前列腺癌患者衍生模型
  • 批准号:
    10683753
  • 财政年份:
    2019
  • 资助金额:
    $ 60.23万
  • 项目类别:
Understanding the role of an aberrant hepatic nuclear transcription circuit in prostate cancer tumorigenesis and castration resistance
了解异常肝核转录回路在前列腺癌肿瘤发生和去势抵抗中的作用
  • 批准号:
    10224110
  • 财政年份:
    2017
  • 资助金额:
    $ 60.23万
  • 项目类别:
Understanding the role of an aberrant hepatic nuclear transcription circuit in prostate cancer tumorigenesis and castration resistance
了解异常肝核转录回路在前列腺癌肿瘤发生和去势抵抗中的作用
  • 批准号:
    9753189
  • 财政年份:
    2017
  • 资助金额:
    $ 60.23万
  • 项目类别:

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