Marie Curie Room, Barcelona Biomedical Research Park (PRBB).

 

 

ABSTRACT

 

The histone modification landscape and spatial organization of the genome regulate gene expression, yet their interplay in colorectal cancer (CRC) progression remains underexplored. In this Thesis, I investigated how the transcriptional and epigenetic layers are modulated in CRC by studying the effects of recurrent mutations in the Apc, Trp53, Smad4 and Kras genes. My findings on healthy and CRISPR-engineered mouse organoids reveal a strong and unexpected widespread impact following APC loss-of-function. p53 silencing also exerts strong changes compared to the limited responses following KRAS-G12D oncoprotein expression and Smad4 mutations. Such changes were consistently observed across transcriptomic data and multiple omics layers, including ATAC-seq, CUT&RUN for H3K27ac and H3K27me3 and in situ Hi-C. The results further suggest that the organoids’ phenotype may be influenced by both the cumulative effect of mutations and the order in which they are acquired. This work provides new insights into the mechanisms underlying CRC initiation and progression from a genome topology perspective.