| First Author | Liang W | Year | 2016 |
| Journal | Int J Clin Exp Pathol | Volume | 9 |
| Issue | 5 | Pages | 5167-5175 |
| Mgi Jnum | J:334153 | Mgi Id | MGI:7447018 |
| Citation | Liang W, et al. (2016) Loss of the epigenetic regulator Ash2l results in desintegration of hepatocytes and liver failure. Int J Clin Exp Pathol 9(5):5167-5175 |
| abstractText | Post-translational modifications of core histones are key to control gene expression. Tri-methylation of lysine 4 of histone H3 (H3K4me3) is associated with active promoters, a modification catalyzed by enzymes of the KMT2 class of lysine specific methyltransferases. These include the mixed lineage leukemia (MLL) and SET1 pro-teins, which represent the catalytic subunits. These are associated with a core complex consisting of WDR5, RbBP5, ASH2L and DPY30. This core complex is thought to be essential for catalytic activity. In order to address the function of the KMT2 complexes in an organism, we have generated a conditional Ash2l knockout mouse. We have crossed these animals with Alb-Cre mice, which express the Cre recombinase under the control of the albumin promoter. This ensures liver specific expression of Cre. We observed efficient deletion of the target region in the Ash2l locus in the liver but not in the spleen. This resulted in a loss of Ash2l expression in hepatocytes and concomitantly a strong reduction in H3K4me3. As a consequence the animals lost weight and an increase of several liver enzymes was detected in the serum, including alkaline phosphatase and aspartate transaminase. The loss of Ash2l was also associated with an increase in Ki-67 positive cells in the liver. Moreover in the few animals that survived more than 4 weeks, we observed an increase in Ceroid-storing macrophages, suggesting that dead hepatocytes are eliminated from the tissue. Together these findings demonstrate that Ash2l is essential for liver function, most likely through an impact on H3K4 methylation. |
