cAMP-PKA regulate the interaction between histone demethylase, LSD1, estrogen receptor-α and the transcription initiation complex

ERα recruits co-activator and transcription factors to the Estrogen Responsive Elements (EREs) to induce transcription. Co-activator complexes facilitate transcriptional activation in part by interacting with chromatin remodeling and histone-modifying enzymes, which render the target chromatin permissive to transcriptional activation. One important protein is LSD1 or KDM1, a flavin adenine dinucleotide-dependent amine oxidase, that catalyzes the removal of methyl groups from di-methylated lysine 4 and lysine 9 in H3 histone, H3K4m2 and H3K9m2, to repress or induce transcription, respectively. The scope of this study is to determine whether cAMP and protein kinase A (PKA) regulate LSD1 and the initiation transcription complex formation. Our data demonstrate that cAMP-PKA phosphorylate LSD1 in threonine 110 and stimulate the interaction with active estrogen receptor α. This event is crucial for the assembly of the transcription initiation complex. We have mapped the region in the receptor necessary for this interaction and we have generated a mutant LSD1 that is not able to interact with the receptor and to stimulate estrogen-dependent transcription. PKA phosphorylates LSD1 at the mapped site (threonine 110) in vitro, and favors the recruitment of factors required for the transcription initiation complex formation. These data illustrate the interplay between two major signaling pathways, estrogens and cAMP-PKA, and how they regulate transcription initiation induced by estrogens