Bertozzo.jpg Supervisore: Prof. Brancolini
Characterization of epigenetic re-organization in tumor context using bioinformatic techniques
Epigenetic alterations play a crucial role in cancer development and progression. Histone modifications, such as histone acetylation, methylation, phosphorylation and ubiquitination can impact chromatin structure and gene accessibility. Dysregulation of histone modification can lead to altered gene expression pattern in cancer cells. Chromatin remodeling complexes can lead to changes in the accessibility of DNA, influencing gene expression, mutations in chromatin remodelers are associated with various cancer types. Also, non-coding RNAs such as miRNAs and lncRNAs are involved in post-trascriptional gene regulation. In this very complex environment, i will focus on the role of Histone Deacetylases (HDACs) enzymes, that are tightly involved in the regulation of gene expression through the removal of acetyl groups on histone proteins. In fact, histone acetylation and deacetylation are dynamic processes that influence chromatin structure and accessibility. Acetylation, and also methylation of histones occurs typically on lysine residues, acetylation is associated with an open chromatin structure and active gene transcription while methylation is associated both to open and close chromatin, depending on the position of lysine residue. HDACs remove acetyl groups from histones, leading to a more condensed chromatin structure and transcriptional repression. Dysregulation of HDAC activity is commonly observed in various cancers. Increased activity of these enzymes in tumoral context can in fact lead to transcriptional repression of tumor suppressor genes, contributing to cancer progression. In the tumoral micro-environment, a characteristic feature is the low oxygen level (hypoxia), due to an inadequate blood supply resulting from rapid tumor growth and abnormal blood vessel formation. Some research has shown that HDACs can modulate the hypoxia response in tumors, directly or indirectly, by influencing the acetylation of histones and non-histone proteins. They can enhance the expression of certain hypoxia-responsive genes, for example HIFs, potentially affecting tumor adaptation to low oxygen environments. The first part of the project will focus on the the interaction of HDACs and hypoxia response. We will conduct experiments of ChIP-seq and RNA-seq, using leiomyosarcoma tumoral cells as model.