机械力学调控多梳基因介导的基因沉默

1、Mechanical regulation of transcription controlspolycomb-mediated gene silencing duringlineage commitmentH Q Le, S Ghatak , CYC Yeung et all.Nature Cell Biology,2016doi:10.1038/ncb33872016.8.23 陈岚Very little is known about the molecular principles underlying the mechanical control of lineage specific

2、ation and maintenance.Non-muscle myosins(NM):a family of motor proteins that generate forces by moving antiparallel actin filaments, are central players in force generation and sensing.Polycomb repressive complex 2 (PRC2)： catalyses dimethylation H3K27me3 through the methyltransferase activity of Ez

3、h1/Ezh26,7, recognizes the untranscribed state of genes to subsequently maintain their repression.Mechanical strain induces transcriptional repressionglobal downregulationof gene expression in strained EPCs5-Ethynyl uridine (EU) incorporation assays show reduced levels of nascent RNA after 12 h of s

4、trainIncreased H3K27me3 and decreased RNAPII-S2p in cells subjected to strainfor 12 hMechanical strain mediates H3K27me3 and RNAPII-S2p occupancyMechanical strain regulates H3K27me3 through localized actinremodelling controlled by Emd and NMIIAStrain increased signal of Emd at the outer nuclear memb

5、rane (ONM) of strained cells whereas the relative signal at the inner nuclear membrane (INM) is decreased ,accumulation of F-actin around the nucleus .RNAi-mediated depletion of Emd (Emd siRNA) prevents actin polymerization at this site.Strain induces Emd-mediated rearrangements of chromatin accompa

6、nied by a switch from H3K9me2,3 to H3K27me3.Increase nuclear actin levels promote productive RNAPII elongationand offset H3K27me3-mediated silencing.Nuclear actin mediates the effect of transcription on H3K27me3 occupancyStrain-induced remodelling of constitutive heterochromatin is independent of th

7、e actin-mediated regulation of RNAPII.Force-mediated adjustment of transcription regulates SC lineage commitmentstrain attenuates EPC lineage progression in an NMII- and PRC2-dependent manner.force-dependent perinuclear actin polymerization mediates the availability of nuclear G-actin to adjust tran

8、scription of PRC2 target genes and thereby EPC lineage commitment.NMIIA activity regulates kinetics of differentiation in vivoThe expression of differentiation gene upregulates in Myh9EKO keratinocytesG-actin levels in basal keratinocytes of Myh9EKO epidermis increased, no differences in the protein levels of the two proteins in strained cells.NMIIA- and Emd-mediated force coupling is required f