Genome Instability in Aging and Disease
Genome instability, i.e., the tendency of the genome to acquire mutations and epimutations, underlies human genetic disease, causally contributes to cancer and has also been implicated in aging and age-related, degenerative conditions other than cancer. Little is known about the mechanisms that give rise to spontaneous changes in the genome or epigenome and how this may lead, in somatic cells, to increased cancer risk and loss of organ and tissue function with age. We study genome and epigenome instability as a function of age in various model organisms, including mouse and fruit fly, and its consequences in terms of alterations in tissue-specific patterns of gene regulation.
In the past we developed transgenic reporter systems in mouse and fruit fly, which allowed us to determine tissue-specific frequencies of various forms of genome instability, e.g., point mutations, deletions, translocations. By crossing the mutational reporter animals with mutants harboring specific defects in various genome maintenance pathways, the relevance of these pathways for the accumulation of specific forms of genome instability is assessed, in relation to the pathophysiology of aging. Similarly, by using knockdown approaches we assess the effect of specific genes implicated in longevity and healthy aging, e.g., SOD, FOXO, SIR2, on genome integrity.
We are currently focused on single-cell genomics to assess mutation frequencies and spectra in human tissues during aging. To gain insight into the possible functional consequences of random somatic mutations we use single-cell multiomics assays to link specific mutations to transcriptional and translational end point.
Projects
NIH Program Project
People
- Yolanne Blake
- Shixiang Sun
- Moonsook Lee
- Zhenqiu Huang
- Alex Maslov
- Johanna Heid
- Yujue Wang
- Julian Gingold
- Olivia Albert
- Ronald Cutler