The Mechanism Study On The Linker Histone H1.2 In The Diabetic Retinopathy And Fatty Liver Disease

Core histones and linker histones are the critical components of the nucleosomes.They regulate the gene expression by maintaining and remodeling the chromatin structure,thus affect multiple cellular processes.Histone H1.2(H1.2)is one of important variants of histone H1,which has been reported to participate in several cellular processes.However,little is known about its role in the human diseases.Here,we studied the roles of H1.2 in the development of diabetic retinopathy and nonalcoholic fatty liver disease(NAFLD)using in vivo and in vitro models.We found that increased autophagy and H1.2 levels in the retinas of type 1 diabetic rodents and high-glucose treated retinal cells.Overexpression of H1.2 promoted the expression of SIRT1 and HDAC1,maintained the deacetylated status of H4K16,led to up-regulation of ATG proteins and autophagy in cultured retinal cell lines.Furthermore,H1.2 overexpression increased inflammation and cell toxicity in cultured retinal cell lines.Knockdown of H1.2 repressed both the basal and stresses(including high-glucose treatment)-induced autophagy,as well as high glucose-induced inflammation and cell toxicity.Importantly,we observed that AAV-mediated hH1.2 overexpression increased autophagy,inflammation,glial activation and neuron loss in the retinas,pathological changes which were similar to those identified in the early stage of diabetic retinopathy.Furthermore,siRNA-mediated knockdown of H1.2 significantly reduced the diabetes-induced autophagy,inflammation,glial activation and neuron loss in the retinas.Taken together,these results suggest that H1.2 plays a critical role in the development of diabetic retinopathy,at least in rodent models.Moreover,we found that overexpression of H1.2 promoted DNA damage and cellular senescence in the retinal cell lines.Knockdown of H1.2 suppressed the DNA damage inducer-and high glucose-induced DNA damage and cellular senescence.Meanwhile,we identified that histone H1.2 bound to PARP-1 and nucleolin.In addition,compared to normal conditions,the interaction between H1.2 and PARP-1 were stronger,while the interaction between H1.2 and nucleolin were weaker,under the stimuli of DNA damage.The globular domain of H1.2 is necessary for its interaction with PARP-1 and nucleolin.Since,PARP-1 and nucleolin have been reported to participate in the DNA damage response,we hypothesized that H1.2 also plays a critical role in the DNA damage response by regulating PARP-1.Finally,H1.2 level was dramatic reduced in the livers of db/db mice and high fat diet(HFD)-fed mice,as well as palmitic acid(PA)-treated cultured hepatic cell lines.H1.2 overexpression repressed the PA-induced lipid accumulation,while knockdown of H1.2 promoted PA-induced lipid accumulation in cultured hepatic cells.As demonstrated by other groups,we also found that autophagy was significantly repressed in the livers of db/db mice and HFD-fed mice.Furthermore,knockdown of H1.2 also repressed autophagy in cultured hepatic cells.Since lipolysis by autophagy has been reported to reduced lipid accumulation,we hypothesized that H1.2 may also participate in the development of NAFLD via regulating autophagy in the hepatocytes.In summary,H1.2 plays critical roles in the development of diabetic retinopathy and NAFLD,which may provide a novel therapeutic target for these diseases.