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The DAXX/ATRX/H3.3 axis in ERV regulation and tumor suppression

DAXX/ATRX/H3.3 轴在 ERV 调节和肿瘤抑制中的作用

基本信息

批准号：
10556315
负责人：
Amanda Rietta Wasylishen
金额：
$ 19.12万
依托单位：
UNIVERSITY OF CINCINNATI
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：
2022-02-01 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10556315
关键词：
ATRX gene Affect Alleles Apoptosis Biochemical Biological Career Transition Award Cells Chromatin Complement Complex DAXX gene DNA DNA Methylation DNA Sequence Alteration DNA Transposable Elements Data Deposition Development Disease Elements Embryo Endocrine Endoderm Epigenetic Process Exhibits Experimental Genetics Foundations Frequencies Functional disorder Funding Gene Expression Profile Genes Genetic Genetic Models Genetic Transcription Genomics Goals Heterochromatin Histones Homeostasis Human Impairment Inflammation Institution Islet Cell Tumor Islets of Langerhans Knockout Mice Laboratories Lead Lesion Link Long Terminal Repeats Malignant Neoplasms Manuscripts Mediating Modeling Molecular Molecular Chaperones Mus Mutate Mutation Neurosecretory Systems Normal tissue morphology Other Genetics Pancreas Pancreatitis Physiological Precision therapeutics Productivity Recovery Recurrence Regenerative response Regulation Reporting Research Role Somatic Cell Stress Telomere Pathway Tissues Transcriptional Silencer Elements Tumor Suppression Tumor Suppressor Proteins Variant cancer heterogeneity career career development cell growth regulation derepression embryonic stem cell epigenetic regulation epigenetic silencing epigenome epigenomics gene function genome sequencing genome-wide histone methylation human disease human model human pluripotent stem cell in vivo in vivo regeneration innovation loss of function mutation mouse genome mouse model novel novel therapeutic intervention permissiveness programs promoter research and development stem cell model telomere tumor tumorigenesis

项目摘要

Project Summary Genome sequencing has implicated novel candidate tumor suppressors, including DAXX and ATRX which are mutated in 43% of pancreatic neuroendocrine tumors (PanNETs). Despite this strong disease association, our understanding of the physiological functions of DAXX and ATRX remains limited. Biochemical and cell biological studies have demonstrated that together they regulate the epigenome as a chaperone complex for the histone variant H3.3, depositing H3.3 in heterochromatin. Additional non-histone chaperone functions have been reported for both genes. We recently developed a conditional mouse model for Daxx and demonstrated that Daxx loss creates a permissive state that cooperates with environmental stress (inflammation) and other genetic lesions (Men1 loss) to affect the transcriptional profile and impact cell state, which ultimately impairs pancreas recovery and regeneration in vivo. The transcriptional changes are associated with dysregulation of ERVs, thereby expanding our understanding of the somatic regulation beyond DNA and histone methylation in vivo, and implicating ERV dysregulation of pancreatic neuroendocrine tumorigenesis. Importantly, we also demonstrated that dysregulation of endogenous genes near ERVs is also observed in human PanNETs with DAXX mutations. This proposal expands on these studies to better understand how mutations in DAXX contribute to tumorigenesis. We will first use our robust physiological mouse models to obtain a comprehensive understanding of the epigenetic mechanisms that underlie ERV dysregulation downstream of Daxx loss. We will conduct an integrative analysis of H3.3 incorporation, DNA methylation, and histone methylation. We will complement these genomic studies with genetic experiments to directly interrogate the Daxx:H3.3 and Daxx:Atrx interactions in vivo using newly generated mouse alleles. Finally, we will extend our studies to an innovative human pluripotent stem cell model that can be differentiated to an endoderm lineage and subsequent pancreas and endocrine cell states. This will reveal context-dependent effects of DAXX loss and illuminate the specific downstream changes that contribute to tumorigenesis. The K22 Career Transition award will not only advance these research objectives, but it will also help achieve my long-term career goal of directing a productive and impactful independent research program focused on the molecular mechanisms that underlie tumorigenesis. Specifically, it will support the establishment of my independent laboratory at a new sponsoring institution. It will further allow for the submission of my first senior author manuscript and provide the foundations and preliminary data to rapidly apply and be competitive for R01 funding. In summary, this proposal supports both research and career development in the epigenetic regulation of cellular homeostasis and how dysregulation contributes to pancreatic neuroendocrine tumorigenesis.

项目总结