Final Report Summary - SET-NET (Enzymatic and genomic targets of histone modifying enzymes and their role in liver metabolism and hepatocarcinogenesis.)
In this program we studied the role of histone methylases and demethylases in liver development, in the pathogenesis of hepatocarcinogenesis and in the regulation of hepatic metabolic pathways. Focus was on Set9, Smyd2 Smyd3, PR-Set7 and LSD1 enzymes. We have generated several mouse models for studying the particular proteins under different physiological and pathological conditions. These models were subjected to extensive analyses using biochemical, proteomics, genomics and cell biology approaches.
The work has unraveled the operation of a complex protein modification network, which involves chromatin structure modifications, transcription factor modifications, alterations in transcription factor cross-regulatory networks and enzymatic cascades of methylating enzymes. These different regulatory levels were found to cooperate at different extent under various conditions, with implications in epigenetic memory, in the regulation of signaling pathways, in maintaining genome stability and metabolic homeostasis. The biological and potential clinical significance of the new regulatory schemes has been established for several of the studied enzymes. These include: the oncogenic function of PR-Set7, Smyd3 and Smyd2; the tumor suppressor function of Set9; the fibrosis promoting role of Set9; the role of PR-Set7 as a major regulator of hepatic glucose and lipid metabolic pathways; the role of LSD1 in adipose tissue function; the role of Set9 in the maintenance of hepatic lipid homeostasis.
The results of the work have been presented in 8 primary scientific publications, 6 review articles in peer-reviewed journals and in 14 scientific conferences. Four additional publications are in preparation or submitted.
The work has unraveled the operation of a complex protein modification network, which involves chromatin structure modifications, transcription factor modifications, alterations in transcription factor cross-regulatory networks and enzymatic cascades of methylating enzymes. These different regulatory levels were found to cooperate at different extent under various conditions, with implications in epigenetic memory, in the regulation of signaling pathways, in maintaining genome stability and metabolic homeostasis. The biological and potential clinical significance of the new regulatory schemes has been established for several of the studied enzymes. These include: the oncogenic function of PR-Set7, Smyd3 and Smyd2; the tumor suppressor function of Set9; the fibrosis promoting role of Set9; the role of PR-Set7 as a major regulator of hepatic glucose and lipid metabolic pathways; the role of LSD1 in adipose tissue function; the role of Set9 in the maintenance of hepatic lipid homeostasis.
The results of the work have been presented in 8 primary scientific publications, 6 review articles in peer-reviewed journals and in 14 scientific conferences. Four additional publications are in preparation or submitted.