The Function And Mechanism Study Of CBP In Mouse Hair Follicle Stem Cell Senescence

Slow the aging process and stay younger is a constant pursuit of human beings.With aging,hair loss is one of the most obvious phonotypes.Numerous studies have demonstrated the important role of epigenetic changes in aging,which is manifested by the increase of heterochromatin formation in nuclei during aging.The formation of heterochromatin plays important roles in suppressing gene transcription and DNA damage repair,and is believed to be critical for stem cell self-renewal and cell fate determination.CBP,a histone acetyltransferase,can regulate histone modification to change chromatin structure.Previous studies have revealed the important function of CBP in hematopoietic stem cell differentiation,neural development and brain aging.However,the role of CBP in aging hair follicle stem cells(HFSCs)remained unclear.In this study,we used Cbp knockout mice to investigate the function and mechanism of Cbp in aging HFSCs.First,immunofluorescence staining of heterochromatin factors in natural aged HFSCs showed that,with the increase of age,heterochromatinization marked by H3K9me3 and HP1 increased and euchromatization marked by H3K27 ac decreased.In addition,the expression of CBP,which is the acetyltransferase of H3K27 ac modification,was also declined with aging.Second,we found that conditional deletion of Cbp triggered an epigenetic switch that mimicked the epigenetic shift in natural aged HFSCs.Loss of Cbp in mice resulted in increased global chromatin compaction and increased spreading of heterochromatin,marked by H3K9me3 and HP1,in euchromatic protein-coding genes,from the promoter to gene body regions.Co-IP assays showed altered compositions of heterochromatin protein complexes,with increased interactions between HP1β/γ and SUV39H2 or TRIM28,which are known responsible for the assembly of heterochromatin,and sc RNA-seq analyses showed the transcriptional repression of genes associated with HFSC proliferation and hair regeneration.The increase in chromatin compaction resulted in repression of G1/S regulator genes and genes associated with hair follicle development,and therefore caused impaired proliferation of HFSCs and arrested telogen-to-anagen transition.Thus,the loss of Cbp induced HFSC exhaustion,hair follicle miniaturization,hair loss and premature aging.Taken together,our study described the epigenetic changes in mouse HFSCs during natural aging,and generated Cbp knockout mice to mimic the phenotype of hair loss in aged mice.We found that Cbp is critical to HFSC proliferation and telogen-to-anagen transition.Furthermore,the findings revealed a novel role of Cbp in limiting facultative H3K9me3-heterochromatin spreading and revealed an epigenetic pathway involved in mammalian adult stem cell aging.