Transdifferentiation of hepatic stellate cells (HSCs) to a myofibroblast-like 
phenotype is the pivotal event in liver fibrosis. The dramatic change in 
phenotype associated with transdifferentiation is underpinned by a global change 
in gene expression. Orchestrated changes in gene expression take place at the 
level of chromatin packaging which is regulated by enzymatic activity of 
epigenetic regulators that in turn affect histone modifications. Using 
expression profiling of epigenetic regulators in quiescent and activated primary 
HSCs we found a number of histone methyltransferases including MLL1, MLL5, Set1 
and ASH1 to be highly up-regulated during transdifferentiation of HSCs. All of 
these histone methyltransferases regulate methylation of lysine 4 of histone H3, 
which is a signature of actively transcribed genes. We therefore postulated that 
one or more of these enzymes may be involved in positively influencing 
expression of profibrogenic genes.
CONCLUSION: We find that ASH1 directly binds to the regulatory regions of alpha 
smooth muscle actin (αSMA), collagen I, tissue inhibitor of metalloproteinase-1 
(TIMP1) and transforming growth factor beta1 (TGFβ1) in activated HSCs while 
depletion of ASH1 caused broad suppression of fibrogenic gene expression. We 
also discovered that MeCP2 positively regulates ASH1 expression and therefore 
identify ASH1 as a key transcriptional activator component of the MeCP2 
epigenetic relay pathway that orchestrates coordinated induction of multiple 
profibrogenic genes.