Summary
This project investigates the molecular mechanisms behind aberrant de novo DNA methylation, specifically CpG island (CGI) hypermethylation, in cancer, focusing on the role of DNMT3A1 and its interactions with histone modifications.
Molecular basis for aberrant de novo DNA methylation in cancer
US · IL
NIH
grant
awarded
#nih-5R01CA266978-04
What they want
The research will test the hypothesis that the redistribution of DNMT3A1 from H3K36 methylation to H2AK119ub-marked CGIs drives CGI hypermethylation and neoplastic transformation. A multidisciplinary approach, leveraging chromatin biochemistry, structural study, cancer biology, and epigenomics, will be employed to reveal the molecular mechanisms of DNMT3A1 regulation by H3K36 methylation and H2AK119Ub, and how the balance between these post-translational modifications mediates DNMT3A1's recruitment, activity, and function in healthy tissues and tumors.
Deliverables
- Enhanced understanding of the dynamics, cause, and consequence of CGI hypermethylation
- Foundation for developing inhibitors targeting the interaction of DNMT3A1 with H2AK119Ub to reverse cancer-associated CGI hypermethylation
Technical requirements
- Chromatin biochemistry expertise
- Structural study expertise
- Cancer biology expertise
- Epigenomics expertise
Key personnel
- Armache lab personnel
- Lu lab personnel
