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The molecular mechanism of Additional sex combs (Asx) in hsp70 transcriptional repression Li, Taosui


Additional sex combs (Asx) is an Enhancer of trithorax and Polycomb (ETP) group gene in Drosophila. Mutations in Asx enhance both trithorax group (trxG) and Polycomb group (PcG) homeotic mutations, suggesting that Asx maintains both activation and repression of homeotic gene transcription. Asx associates with Trithorax (Trx) in vivo and is required for promoter clearance at the homeotic gene Ultrabithorax (Ubx). Asx is necessary for the heat shock response and is recruited to the heat shock inducible gene hsp70 promoter region following heat stress. Mutations in Asx resulted in a 2-fold increase of the hsp70 mRNA level upon heat shock induction compared to wild-type, indicating that Asx is a transcriptional repressor at hsp70 during heat shock induction and recovery. To gain further insights into the molecular mechanism of Asx as a transcriptional repressor at the hsp70 locus, the effect of Asx on the transcriptional activation marker, histone H3K4 trimethylation, and the repression marker, histone H3K27 trimethylation, were investigated. Asx prevented the deposition of histone H3K4 trimethylation and promoted histone H3K27 trimethylation deposition at hsp70 during heat shock induction and recovery. I propose that Asx prevents Trx-mediated trimethylation of H3K4 and prevents transcriptional elongation, which indirectly promotes the activity of PRC2-mediated transcriptional repression. At the early stage of hsp70 heat shock induction, Asx-mediated repression likely plays a role in blocking the recruitment of Heat shock factor (HSF), Mediator or elongation factors rather than altering histone H3K4 or H3K27 trimethylation levels. Combined with other studies in the lab on Ubx, we can for the first time propose testable models for Asx function as an ETP.

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