Waddington Revisited: Organ transformation by environmental disruption of epigenetic memory

Despite major progress in mechanistic understanding of epigenetic reprogramming of cells, the basis of organ reprograming by (epi-)gene-environment interactions remained largely obscured. Here we use the ether-induced haltere-to-wing transformations as a model for epigenetic "reprogramming" at the whole organism level. Our findings support a mechanistic chain of events explaining why and how brief embryonic exposure to ether leads to organ transformation manifested at the larval stage and on. We show that ether interferes with protein integrity in the egg leading to altered deployment of Hsp90 and repression of Trithorax-mediated establishment of H3K4 tri-methylations. This repression pre-disposes early methylated Ubx targets and wing genes for later up-regulation in the larval haltere disc, hence the wing-like outcome. Consistent with compromised protein integrity during the exposure, the severity of bithorax transformation is increased by genetic or chemical reduction of Hsp90 function. Moreover, a joint reduction in Hsp90 and trx gene dosage can cause bithorax transformations without exposure to ether. These findings implicate environmental disruption of protein integrity at the onset of histone methylations with a modification of epigenetic memory, which in turn, supports a morphogenetic shift towards an ancestral-like body plan. The morphogenetic impact of chaperone response during a major setup of epigenetic patterns may be a general scheme for organ reprogramming by environmental cues.