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

Abstract

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.

Emerging Role of HDACs in Regeneration and Ageing in the Peripheral Nervous System: Repair Schwann Cells as Pivotal Targets

“…Recent work carried out by Velasco–Aviles et al (2022) focusing on class II HDACs has shown that they also play an important role in repair SC biology and remyelination, in particular Hdac4 , Hdac5 , and Hdac7 , which are expressed in SCs [ 6 ]. In a SC-specific triple cKO of these HDACs, using Mpz -Cre mice, they saw that remyelination is impaired, but repair SC activation is accelerated due to increased myelin clearance in mutant mice after injury.…”

“…Hdac4/5/7 tKO mice show elevated JUN levels after nerve injury, and this JUN upregulation has been shown to delay remyelination in nerve regeneration, the same delay seen in Jun _OE overexpressing mice [ 64 ]. In injured nerves of single cKO for Hdac5 and Hdac7 , Velasco et al (2022), did not find a significant effect on remyelination or in repair SC activation, and in Hdac4 single cKO there was only a slight delay in remyelination, but not in repair SC activation [ 6 ].…”

“…In Class IIa HDACs, genetic compensation has recently been reported as well. Velasco-Aviles et al (2022) describe genetic redundancy in repair SCs (as well as in development, see Section 2.2 ) using cKO in Mpz -Cre mice [ 6 ]. In regeneration and during remyelination, single cKO of Hdac4 , Hdac5 , or Hdac7 does not have any effect on remyelination.…”

“…Specifically, HDACs are needed to repress the Jun promoter and, therefore, allow myelination to proceed [ 4 ]. HDAC downregulation is also important in repair SCs, as it has been shown that when certain HDACs are depleted in SCs, remyelination, as well as the induction of the repair program, are affected [ 5 , 6 ].…”

“…Furthermore, there is redundancy in HDAC expression, suggesting that there is genetic compensation of HDACs in the PNS: when one HDAC is depleted, another is upregulated, and consequently peripheral nerve myelination and maintenance is conserved [ 6 ].…”