A specific mechanism for ethionine-induced embryonic gene activity.
A specific mechanism was given for ethionine-induced alpha-fetoprotein gene activity and is as follows: 1. Ethionine acts on competent cell types (e.g. stem cells) having one alpha-fetoprotein-enhancer-albumin gene region that is active and possesses embryonic-like low levels of S-adenosyl-L-methionine synthesis: DNA methylase genes for the enhancer regions are in the heterochromatic state. 2. ATP: L-methionine-S-adenosyltransferase acts upon ethionine and ATP to form S-adenosyl-L-ethionine; this lowers the amount of S-adenosyl-L-methionine synthesized and in turn also the synthesis of methyl-nicotinamide; the concentration of nicotinamide increases; there is an inhibition of polyADP ribosylation; hyporibosylation of histone 1 of nucleosomes; deblocking of embryonic type heterochromatin; and finally the second alpha-fetoprotein gene becomes activated. 3. Reversal occurs with the introduction of methionine; increase of S-adenosyl-L-methionine synthesis; increased methylnicotinamide synthesis; increased polyADP-ribose synthesis; ribosylation of H-1 protein to normal levels; and then the packing configuration of chromatin causes rerepression of alpha-fetoprotein genes. It is suggested that ethionine has the ability to perturb a methyl-sensitive heterochromatin that is peculiar to chromatin synthesized during embryogenesis. Therefore such repressed embryonic genes as alpha-fetoprotein are differentially susceptible to low concentrations of active methyl groups. Ethionine causes this hypomethylated heterochromatin by interference with S-adenosyl-L-methionine synthesis.
Hancock
R L
RL
Canadian Institute of Theoretical Biology, Nova Scotia.
D000241:Adenosine / Q000031:analogs & derivatives / Q000378:metabolism; D000818:Animals; D004622:Embryo, Mammalian / Q000378:metabolism; D004625:Embryo, Nonmammalian; D005001:Ethionine / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced; D008954:Models, Biological; D012436:S-Adenosylmethionine / Q000378:metabolism; D000509:alpha-Fetoproteins / Q000235:genetics*
D000509:alpha-Fetoproteins; C012167:S-adenosylethionine; D012436:S-Adenosylmethionine; D000241:Adenosine; D005001:Ethionine