Chd7 Collaborates with Sox2 to Regulate Activation of Oligodendrocyte Precursor Cells after Spinal Cord Injury

Abstract

Oligodendrocyte precursor cells (OPCs) act as a reservoir of new oligodendrocytes (OLs) in homeostatic and pathological conditions. OPCs are activated in response to injury to generate myelinating OLs, but the underlying mechanisms remain poorly understood. Here, we show that chromodomain helicase DNA binding protein 7 (Chd7) regulates OPC activation after spinal cord injury (SCI). Chd7 is expressed in OPCs in the adult spinal cord and its expression is upregulated with a concomitant increase in Sox2 expression after SCI. OPC-specific ablation of Chd7 in injured mice leads to reduced OPC proliferation, the loss of OPC identity, and impaired OPC differentiation. Ablation of Chd7 or Sox2 in cultured OPCs shows similar phenotypes to those observed in knock-out mice. Chd7 and Sox2 form a complex in OPCs and bind to the promoters or enhancers of the () and θ (θ) genes, thereby inducing their expression. The expression of Rgcc and PKCθ is reduced in the OPCs of the injured knock-out mice. In cultured OPCs, overexpression and knock-down of Rgcc or PKCθ promote and suppress OPC proliferation, respectively. Furthermore, overexpression of both Rgcc and PKCθ rescues the Chd7 deletion phenotypes. Chd7 is thus a key regulator of OPC activation, in which it cooperates with Sox2 and acts via direct induction of Rgcc and PKCθ expression. Spinal cord injury (SCI) leads to oligodendrocyte (OL) loss and demyelination, along with neuronal death, resulting in impairment of motor or sensory functions. Oligodendrocyte precursor cells (OPCs) activated in response to injury are potential sources of OL replacement and are thought to contribute to remyelination and functional recovery after SCI. However, the molecular mechanisms underlying OPC activation, especially its epigenetic regulation, remain largely unclear. We demonstrate here that the chromatin remodeler chromodomain helicase DNA binding protein 7 (Chd7) regulates the proliferation and identity of OPCs after SCI. We have further identified regulator of cell cycle (Rgcc) and protein kinase Cθ (PKCθ) as novel targets of Chd7 for OPC activation.

Influence of white matter injury on gray matter reactive gliosis upon stab wound in the adult murine cerebral cortex

“…In addition to the regulation and effect of MIF discussed above, we also observed a differential abundance of the Dickkopf3‐related protein 3 (DKK3) to be enriched in the GM− injury which may indicate increased levels of Wnt‐signaling regulating NG2 glia proliferation after injury (Rodriguez et al, ) in addition to MIF. Interestingly, the Chromodomain Helicase DNA Binding Protein 7 (CHD7) is also regulated by MIF that is involved amongst other functions in regulating myelination (Doi et al, ; He et al, ). This is interesting as we found several proteins promoting oligodendrocyte differentiation indicative of increased myelination to be enriched in the GM+ injury with reduced NG2 glia proliferation.…”

Epigenetic modifications—insight into oligodendrocyte lineage progression, regeneration, and disease

“…Unexpectedly, CHD7 expression is highly enriched in oligodendrocyte lineage cells in the CNS, with a peak of expression in differentiating oligodendrocytes. Inactivation of CHD7 in mice causes a delay in oligodendrocyte differentiation and myelination since CHD7 cooperates with Sox10 to activate myelin‐associated gene expression; however, CHD7 inactivation does not seem to affect OPC formation in vivo , despite a defect in OPC proliferation .…”

“…Furthermore, CHD7 is analogously critical for remyelination after demyelinating injury , consistent with the notion that oligodendrocyte lineage development is recapitulated in regeneration. Notably, CHD7 can cooperate with Sox2 to activate OPC proliferation after spinal cord injury in mice . Despite being unnecessary for OPC formation, CHD7 ablation leads to impaired OPC differentiation during remyelination after lysolecithin‐induced demyelination as well as reduced OPC recruitment and differentiation after spinal cord injury by laminectomy .…”

“…Notably, CHD7 can cooperate with Sox2 to activate OPC proliferation after spinal cord injury in mice . Despite being unnecessary for OPC formation, CHD7 ablation leads to impaired OPC differentiation during remyelination after lysolecithin‐induced demyelination as well as reduced OPC recruitment and differentiation after spinal cord injury by laminectomy . In addition, CHD7 appears to collaborate with Sox10 and Sox2 to regulate OPC differentiation and activation, respectively, and is therefore an important determinant of effective myelin repair.…”

“…CHD7 targets the enhancers of Myrf and Olig1 and promotes their expression to induce oligodendrocyte maturation . Besides its role in OPC differentiation, CHD7 appears to regulate OPC proliferation through activating expression of PKCΘ and Rgcc (regulator of cell cycle) . In addition, CHD7 can target and regulate other oligodendrocyte maturation‐associated factors such as Osterix/Sp7 and Creb3 l2, which are also critical for bone formation .…”