Epigenetic mechanisms in human disease and the development of epigenetic therapeutic approaches.
My particular interest is in investigating the molecular mechanisms by which nuclear architecture, transcriptional regulation and epigenetics can be causative of a disease phenotype and how this can be targeted for therapy of human disorders.
1. Epigenetic control of house-keeping genes by Sp1 and histone acetylation: molecular mechanisms and therapeutic potential.
Transcription factor binding and chromatin accessibility seen as histone acetylated regions on the promoter are the prerequisite for active transcription.
We are interested in understanding the function that HDAC inhibitors play in the reversible de-repressive epigenetic state and as a result, the reversion of the phenotype. Understanding the HDAC inhibitors molecular mechanisms of action can open the possibility for using them in a broader type of diseases, and not only when there is deregulation of gene expression.
2. The impact of a disease-causing mutation/chromosomal translocation on the genomic interactome and its role on the disease phenotype.
We speculate that genes are not transcribed linearly and in isolation but instead can be part of more complex, multi-gene transcriptional units where enhancers play a crucial cell-lineage specific role. This would require the active genes/enhancers to loop out of their chromosomal territories forming supranuclear domains that are non random and can have a regulatory role.
3. Potent in vitro and in vivo anti-myeloma activity of BET inhibitors
BET inhibitors have shown significant anti-tumour and anti-inflammatory activity assessed in preclinical models of leukaemia, sepsis and autoimmune disease. We set to study the in vitro and in vivo activity of the I-BET compounds against multiple myeloma, and explore its molecular mechanism of action.
4. Effect of I-BET compounds on osteoclast activation and bone disease in multiple myeloma
Based on these anti-myeloma effect of I-BET, we predict that I-BET will have a significant inhibitory effect on osteoclast differentiation and in particular activation. We propose to conduct a preliminary study to investigate the effect of I-BET on basal bone homeostasis as well as on myeloma-related bone disease.
5. Role of transcription factors and chromatin regulators in myeloma survival and proliferation
Karadimitris A, 2021, Chromatin-based, in cis and in trans regulatory rewiring underpins distinct oncogenic transcriptomes in multiple myeloma, Nature Communications, ISSN:2041-1723
et al., 2021, Single-cell profiling of human bone marrow progenitors reveals mechanisms of failing erythropoiesis in Diamond-Blackfan anemia, Science Translational Medicine, Vol:13, ISSN:1946-6234
et al., 2021, Systems level profiling of chemotherapy-induced stress resolution in cancer cells reveals druggable trade-offs, Proceedings of the National Academy of Sciences of Usa, Vol:118, ISSN:0027-8424
et al., 2021, Role of Polymorphisms of NKG2D Receptor and Its Ligands in Acute Myeloid Leukemia and Human Stem Cell Transplantation, Frontiers in Immunology, Vol:12, ISSN:1664-3224
et al., 2021, The innate sensor ZBP1-IRF3 axis regulates cell proliferation in multiple myeloma., Haematologica