Genome-wide dysregulation of R-loops in Ataxia Telangiectasia neurological pathogenesis

共济失调毛细血管扩张症神经发病机制中 R 环的全基因组失调

基本信息

  • 批准号:
    10607414
  • 负责人:
  • 金额:
    $ 4.77万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2023
  • 资助国家:
    美国
  • 起止时间:
    2023-03-13 至 2026-01-12
  • 项目状态:
    未结题

项目摘要

Project Abstract: Ataxia Telangiectasia (AT), a multisystemic neurodegenerative disease characterized by decreasing motor coordination, mental development, immune defects, and telangiectasia of the eyes, affects up to 1 in 40,000 to 100,000 people worldwide. A recessive early childhood onset disorder, AT is caused by mutations within the ataxia telangiectasia mutated (ATM) threonine/serine kinase which plays crucial roles within the DNA damage response (DDR). However, the precise molecular mechanisms underlying AT pathogenesis and how ATM loss- of-function leads to deficient DDR remain elusive. R-loops, three stranded RNA-DNA structures composed of an DNA-RNA hybrid and a non-template DNA strand, have emerged as key components of double strand break (DSB)-induced DDR. Mounting evidence has documented critical roles of R-loops in both causing and responding to DSBs. As DSBs and the failure of their repair play major roles in the pathology of AT, R-loop dysregulation is likely to contribute to AT pathogenesis. One recently identified kinase substrate of ATM is methyltransferase like 3 (METTL3) protein, a N6-methyladenosine (m6A) methyltransferase. m6A on the RNA strand of R-loops is present inside nuclei and affects R-loop formation during DSB repair. The relationship between ATM-METTL3 phosphorylation in response to DNA damage and regulation of R-loop formation, which could play crucial roles in AT pathogenesis, has yet to be defined. Our preliminary data has demonstrated a global trend of R-loops decreasing in AT patient-derived neurons compared to healthy controls. ~20% of these lost loci were rescued in an isogenic line where the ATM mutation had been corrected. We hypothesize that in AT, the lack of METTL3 phosphorylation by ATM could globally dysregulate R-loop formation and underly AT progression. In Aim 1 we will investigate the global landscape of R-loops and analyze their effect on gene expression and chromatin accessibility throughout neuronal differentiation in healthy, AT-derived, and isogenic neurons. In Aim 2, we will define how ATM-mediated phosphorylation of METTL3 impacts the formation of R- loops. We will generate iPSC-derived motor neurons from age-matched healthy controls, AT patients, and their isogenic lines with the pathogenic mutations corrected by genome editing to systematically identify critical R- loop loci that are associated with AT and mechanistically explore the role of ATM truncations in AT progression through METTL3-dependent R-loop regulation.
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项目成果

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