A genetic compensatory mechanism regulated by Jun and Mef2d modulates the expression of distinct class IIa Hdacs to ensure peripheral nerve myelination and repair

The class IIa histone deacetylases (HDACs) have pivotal roles in the development of different tissues. Of this family, Schwann cells express Hdac4, 5, and 7 but not Hdac9. Here, we show that a transcription factor regulated genetic compensatory mechanism within this family of proteins, blocks negative regulators of myelination ensuring peripheral nerve developmental myelination and remyelination after injury. Thus, when Hdac4 and 5 are knocked-out from Schwann cells in mice, a JUN-dependent mechanism induces the compensatory overexpression of Hdac7 permitting, although with a delay, the formation of the myelin sheath. When Hdac4, 5, and 7 are simultaneously removed, the myocyte-specific enhancer-factor d (MEF2D) binds to the promoter and induces the de novo expression of Hdac9, and although several melanocytic lineage genes are misexpressed and Remak bundle structure is disrupted, myelination proceeds after a long delay. Thus, our data unveil a finely tuned compensatory mechanism within the class IIa Hdac family, coordinated by distinct transcription factors, that guarantees the ability of Schwann cells to myelinate during development and remyelinate after nerve injury.This work has been funded by grants from the Ministerio de Economía y Competitividad (BFU2016-75864R and PID2019-109762RB-I00), ISABIAL (UGP18-257 and UGP-2019–128) to H Cabedo, and Conselleria Educació Generalitat Valenciana (PROMETEO 2018/114) to J Gallar and H Cabedo. Predoctoral fellowships ACIF/2 017/169 from Generalitat Valenciana (to L Frutos-Rincón) and FPU16/00283from Ministerio de Universidades are also acknowledged. The Instituto de Neurociencias is a 'Center of Excellence Severo Ochoa' (Ministerio de Economía y Competitividad SEV-2013-0317).Peer reviewe