A PHD12-Snail2 repressive complex epigenetically mediates neural crest epithelial to mesenchymal transition

STROBL MAZZULLA, P.H.; BRONNER-FRASER, M.

JOURNAL OF CELL BIOLOGY

ROCKEFELLER UNIV PRESS

Lugar: New York; Año: 2012 vol. 198 p. 999 - 1010

0021-9525

Neural crest cells form within the neural tube andthen undergo an epithelial to mesenchymal transition(EMT) to initiate migration to distant locations.The transcriptional repressor Snail2 has beenimplicated in neural crest EMT via an as of yet unknownmechanism. We report that the adaptor protein PHD12 ishighly expressed before neural crest EMT. At cranial levels,loss of PHD12 phenocopies Snail2 knockdown, preventingtranscriptional shutdown of the adhesion moleculeCad6b (Cadherin6b), thereby inhibiting neural crest emigration.Although not directly binding to each other,PHD12 and Snail2 both directly interact with Sin3A invivo, which in turn complexes with histone deacetylase(HDAC). Chromatin immunoprecipitation revealed thatPHD12 is recruited to the Cad6b promoter during neuralcrest EMT. Consistent with this, lysines on histone 3 at theCad6b promoter are hyperacetylated before neural crestemigration, correlating with active transcription, butdeacetylated during EMT, refl ecting the repressive state.Knockdown of either PHD12 or Snail2 prevents Cad6bpromoter deacetylation. Collectively, the results show thatPHD12 interacts directly with Sin3A/HDAC, which in turninteracts with Snail2, forming a complex at the Cad6bpromoter and thus revealing the nature of the in vivo Snailrepressive complex that regulates neural crest EMT.