Incorporation of a histone mutant with H3K56 site substitution perturbs the replication machinery in mouse embryonic stem cells

Sense mutations in several conserved modifiable sites of histone H3 have been found to be strongly correlated with multiple tissuespecific clinical cancers.These clinical site mutants acquire a distinctively new epigenetic role and mediate cancer evolution.In this study,we mimicked histone H3 at the 56th lysine(H3K56)mutant incorporation in mouse embryonic stem cells(mESCs)by lentivirus-mediated ectopic expression and analyzed the effects on replication and epigenetic regulation.The data show that two types of H3K56 mutants,namely H3 lysine 56-to-methionine(H3K56M)and H3 lysine 56-to-alanine(H3K56A),promote replication by recruiting more minichromosome maintenance complex component 3 and checkpoint kinase 1 onto chromatin compared with wild-type histone H3 and other site substitution mutants.Under this condition,the frequency of genomic copy number gain in H3K56M and H3K56A cells globally increases,especially in the Mycl1 region,a known molecular marker frequently occurring in multiple malignant cancers.Additionally,we found the disruption of H3K56 acetylation distribution in the copy-gain regions,which indicates a probable epigenetic mechanism of H3K56M and H3K56A.We then identified that H3K56M and H3K56A can trigger a potential adaptation to transcription;genes involved in the mitogen-activated protein kinase pathway are partially upregulated,whereas genes associated with intrinsic apoptotic function show obvious downregulation.The final outcome of ectopic H3K56M and H3K56A incorporation in mESCs is an enhanced ability to form carcinomas.This work indicates that H3K56 site conservation and proper modification play important roles in harmonizing the function of the replication machinery in mESCs.

Connection between earthquakes and deep fluids revealed by magnetotelluric imaging in Songyuan,China

Songyuan is the most earthquake prone area in northeast China.Since 2006,earthquakes have occurred in the area in the form of swarms,with a maximum magnitude of M_L5.8.There is much controversy about the cause of the Songyuan earthquakes.We attempted to determine the cause using a three-dimensional electrical conductivity structure inverted from a regional network of magnetotelluric data in the Songyuan area.The L-BFGS inversion method was applied,with a fullimpedance tensor data set used as the inversion input.Combined with an evaluation of the earthquake locations,the resistivity model revealed a northeast-oriented hidden fault running through the Songyuan earthquake area(SEA),which was speculated to be the preexisting Fuyu-Zhaodong Fault(FZF).Our resistivity model also found an apparent lithospheric low-resistivity anomaly beneath the earthquake area,which breached the high-resistivity lithospheric mantle and stalled at the base of the crust.A petrophysical analysis showed that this lower crustal low-resistivity anomaly was most likely attributed to hydrated partial melting,which could release water into the lower crust during later magma emplacements.While weakening the strength of the FZF,these ascending fluids also increased the pore pressure in the fault,further reducing the shear strength of the fault.Shear stress action(a fault strike component of the east-west regional compress),together with possible near-surface disturbances,may drive the fault to slip and trigger the earthquakes in Songyuan.It is possible that the continuous replenishment of fluids from the deeper mantle forces the Songyuan earthquakes into the form of swarms.We infer that the Songyuan earthquakes could be attributed to a combination of preexisting faults,regional stress,and deep fluids associated with plate subduction,and near surface disturbances might induce the earthquakes in advance.The Songyuan earthquakes are inherently induced earthquakes,fed by deep fluids.