Histone H3 lysine 4 demethylation is a target of nonselective antidepressive medications.
Demethylation of histone H3 lysine 4 is carried out by BHC110/LSD1, an enzyme with close homology to monoamine oxidases (MAO). Monoamine oxidase A or B are frequent targets of selective and nonselective small molecular inhibitors used for treatment of depression. Here we show that in contrast to selective monoamine oxidase inhibitors such as pargyline, nonselective monoamine oxidase inhibitors potently inhibit nucleosomal demethylation of histone H3 lysine 4. Tranylcypromine (brand name Parnate) displayed the best inhibitory activity with an IC50 of less than 2 microM. Treatment of P19 embryonal carcinoma cells with tranylcypromine resulted in global increase in H3K4 methylation as well as transcriptional derepression of two BHC110 target genes, Egr1 and the pluripotent stem cell marker Oct4. These results attest to the effectiveness of tranylcypromine as a small molecular inhibitor of histone demethylation.
Lee
Min Gyu
MG
The Wistar Institute, 3601 Spruce Street, Philadelphia, Pennsylvania 19104, USA.
Wynder
Christopher
C
Schmidt
Dawn M
DM
McCafferty
Dewey G
DG
Shiekhattar
Ramin
R
D000581:Amidohydrolases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000928:Antidepressive Agents / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D006657:Histones / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D008239:Lysine / Q000378:metabolism*; D008745:Methylation / Q000187:drug effects; D015394:Molecular Structure; D008995:Monoamine Oxidase / Q000378:metabolism; D008996:Monoamine Oxidase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D009707:Nucleosomes / Q000187:drug effects / Q000378:metabolism; D014191:Tranylcypromine / Q000494:pharmacology
D000928:Antidepressive Agents; D004791:Enzyme Inhibitors; D006657:Histones; D008996:Monoamine Oxidase Inhibitors; D009707:Nucleosomes; D014191:Tranylcypromine; D008995:Monoamine Oxidase; D000581:Amidohydrolases; D008239:Lysine