Ayoub Nabieh , Associate Professor
We aim to better understand the mechanisms through which chromatin abnormalities are linked to chromosomal instability, cancer and other human diseases. The main research interest of my lab focuses on the biology of histone methylation/demethylation and their link to cancer, with particular emphasis on KDM4A-D histone demethaylases family.
Aberrant histone modifications are a common hallmark of human cancer cells and implicated in the tumorigenic process. Two lines of evidence have specifically implicated the repressive methylation mark of H3K9 in chromosomal instability and predisposition to cancer. First, mice deficient for histone methyl-transferase (KMT) SUV39h1 and SUV39h2, that selectively methylate H3K9, show an increased incidence of tumors. Second, loss of these epigenetic marks by over-expression of the lysine demethylases KDM4A-D (which selectively demethylates H3K9me2/me3 and H3K36me2/me3 marks), is associated with genomic instability and predisposition to cancer. A combination of techniques including somatic genetic, interventional microscopy and high throughput genomics and proteomics assays will be used to elucidate the mechanisms of genome instability triggered by KDM4A-D demethylases. The specific goals of our work are :
i) To elucidate KDM4’s dynamic behaviour in the nucleus of living cells both during a normal cell cycle and in response to DNA damage.
ii) To map sites of post translational modifications on KDM4A-D family and assess their role on modulating their demethylase activity.
iii) To identify non-histone substrates of KDM4A-D demethylases.
iv) To map the chromatin binding sites of KDM4A-D in a genome-wide manner.
v) To assess the role of KDM4A-D in carcinogenesis in-vivo using a mouse model.