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HISTONE MODIFICATIONS AND STEM CELL MAINTENANCE

Dr Herceg further explored the role of histone acetylation in conditional TRRAP KO mice: “TRRAP is important for development, therefore the KO mice could not develop beyond a certain stage of embryogenesis. With this model we could inactivate the gene in a so-called conditional manner, in specific cell types and developmental stages. We studied the consequences of gene inactivation and its effect on the epigenome or transcriptome. We were surprised to find that inactivation of TRRAP in hematopoietic stem cells leads to their death, implying that in tissue-specific stem cells this gene might be important for survival [1]. But when we inactivated the gene in the embryonic stem cells in a conditional manner, we observed unscheduled differentiation, indicating that in embryonic stem cells this gene functions in maintaining so-called stem cell features, illustrating the tissue specificity of this gene and other gene families”.

As expected, deleting the HAT cofactor TRRAP led to a loss of histone acetylation in cells and an increase in histone methylation (so-called silent marks). At the histone architecture level we see compaction of chromatin structure, heterochromatization, which suggests that at the global genomic level there are histone modifications and gene expression-reprogramming. “We observed an expression of some differentiation genes and shut down of stemness genes. We also looked at the global binding pattern of the TRRAP proteins throughout the genome, in stem cells versus differentiated cells. Interestingly, we found that the binding of TRRAP overlaps significantly with stemness genes on a genome-wide scale. When the cell differentiates we lose this co-presence on the same promoters. This suggests that histone acetylation is important for regulating the expression and function of the stemness genes, and maintenance of their self renewal”, states Dr Herceg.

Dr Herceg continues: "We are characterizing this interaction between the HAT complexes and the so-called stemness genes. The other research line is to understand the structure, function, and interactions of the TRRAP protein. TRRAP has multiple roles and a number of interacting proteins, among which protooncogenes like c-Myc. Therefore it could have a dual role, being essential for transformation but also having tumor suppressor features, thus it represents a potential target for some therapeutic intervention. "

How histone acetylation operates in cancer stem cells has not been characterized yet. But for Dr Herceg, it is an interesting question, especially regarding the cancer stem cell hypothesis: “Cancer stem cells may originate from differentiated cells through de-differentiation, but they could also be generated from cancer cells, or they are aberrant tissue-specific stem cells. I tend to think that normal tissue specific stem cells, but also progenitors, (immature cells that are differentiated to some extent), may acquire a set of epigenetic and genetic changes that would lead them towards oncogenic transformation. They would display these features of self renewal but also the capacity to recapitulate cancer heterogeneity. So understanding this and how the tissue specific stem cells are regulated, may help us to better understand the mechanisms by which cancer stem cells develop."

[1] J.I. Loizou and al, J Immunol, 2009