Genome organization during hepatocarcinogenesis

ESPINOSA L.; TORRES-FUENZALIDA J.; PARADA L.

Corrientes

Congreso; XL Congreso Argentino de Genética; 2011

Sociedad Argentina de Genética

Hepatocellular carcinoma (HCC) is one of the most common human malignancies worldwide. Decreased activity of Methionine Adenosyl Transferase 1A (MAT I y Mat III), the liver specific form of MAT, has been demonstrated in various liver diseases, including HCC. MAT1A knockout mice develop hepatic steatosis (HS) after 3 months, non alcoholic steatohepatitis (NASH) after 8 months, and HCC after 12 moths in a step wise fashion. Hepatocytes from 4, 8 and 12 month-old wild type (WT) and MAT1A-KO male mice were subjected to metaphase and interphase genome analysis. Spectral karyotyping showed clonal losses of chromosomes 17, 18, 19 in 50% of animals with HS. These numerical abnormalities were present in all mice with NASH, accompanied by recurrent chromosome structural changes and unidentifiable markers denoting chromosome fusion. 3-D analysis of the nuclear architecture showed that the fraction of the nuclear volume occupied by chromocenters in hepatocytes from MAT1A-KO mice increased with the progression of the disease, contrasting with age matched WT mice in which decreased with age. Telomere length measurement on metaphase chromosomes showed that it decreases significantly in animals with NASH compared to HS, but elongation seems to happen after HCC onset. However, volume measurements revealed that the fraction of the nuclear volume occupied by telomeres in interphase increases. Finally, comparison of the histone H3-K9 acethylation level of hepatocytes from mice at different stages of liver disease demonstrated a trend of hyperacethylation during tumor development. Taken together, these data indicates that the malignant progression in MAT1A-KO mice involves global genome organization changes affecting centromeres, telomeres and chromosome arms.