Explore The Role Of Setdbl In The Development And Regeneration Of Myelin In CNS Of Mice

With the research about epigenetics becoming more and more deeply,many results show that histone modifications are involved in the process of gene transcriptional regulation,tissue development and tumor generation.It is reported that Setdb1,a histone methyltransferase,can regulate the differentiation of neural stem cells into neurons during embryonic development.The deletion of HDAC1/HDAC2 in OPCs can block their differentiation into oligodendrocyte,resulting the loss of myelin in mice.Both Setdb1 and HDAC1/HDAC2 are involved in epigenetic modifications of histone,so we speculate that Setdb1 is likely to have a similar role in regulating the development of oligodendrocytes.We have found that systemic knockout of Setdb1 can lead to death in mouse embryos,so Cre/LoxP recombinant enzyme system is selected to study the role of Setdb1 in the development of oligodendrocytes.In the process of the formation of myelin in juvenile mice,we found that after the specific knockout of Setdb1 in OPCs,mutant mice could be born normally,but the symptoms of the absence of myelin,such as tremor,convulsion,were displayed about ten days after birth,and mutant mice died about 20 days after the birth.Anatomical experiments found that the optic nerve and spinal cord of mutant mice were almost transparent,and the immunohistochemical staining proved that the absence of myelin was caused by a large decrease of oligodendrocytes.At the same time,the number of OPC lineage cells decreased significantly with the number of astrocytes increasing.But the survival and proliferation of OPCs were not affected,and the development of neurons was not influenced either.Obviously,these results indicate that the process of OPCs differentiating into oligodendrocytes is obstructed.In the process of regeneration of myelin in adult brain-injured mice,we found that the specific knockout of Setdbl in OPC lineage cells did not cause the demyelination of the established myelin,but newborn myelin in the injured region of mutant mice was reduced,and the thickness of myelin sheath became thinner.The newborn oligodendrocytes also decreased.These data indicates that the process of OPCs differentiating into oligodendrocytes is blocked in the injured area of mutant mice.Our experiments show that Setdb1 is necessary for myelination generation and regeneration in mice.This also indicates that it has an irreplaceable role in the development of oligodendrocytes.And the result lays the foundation for subsequent experiments.