Human leukocyte antigen(HLA)disparity between donors and recipients is a key determinant triggering intense alloreactivity,leading to a lethal complication,namely,acute graft-versus-host disease(aGVHD),after allogenei...Human leukocyte antigen(HLA)disparity between donors and recipients is a key determinant triggering intense alloreactivity,leading to a lethal complication,namely,acute graft-versus-host disease(aGVHD),after allogeneic transplantation.Moreover,aGVHD remains a cause of mortality after HLA-matched allogeneic transplantation.Protocols for HLA-haploidentical hematopoietic cell transplantation(haploHCT)have been established successfully and widely applied,further highlighting the urgency of performing panoramic screening of non-HLA variations correlated with aGVHD.On the basis of our time-consecutive large haploHCT cohort(with a homogenous discovery set and an extended confirmatory set),we first delineated the genetic landscape of 1366 samples to quantitatively model aGVHD risk by assessing the contributions of HLA and non-HLA genes together with clinical factors.In addition to identifying multiple loss-of-function(LoF)risk variations in non-HLA coding genes,our data-driven study revealed that non-HLA genetic variations,independent of HLA disparity,contributed the most to the occurrence of aGVHD.This unexpected major effect was verified in an independent cohort that received HLA-identical sibling HCT.Subsequent functional experiments further revealed the roles of a representative non-HLA LoF gene and LoF gene pair in regulating the alloreactivity of primary human T cells.Our findings highlight the importance of non-HLA genetic risk in the new era of transplantation and propose a new direction to explore the immunogenetic mechanism of alloreactivity and to optimize donor selection strategies for allogeneic transplantation.展开更多
The accurate chromatin states are essential for maintaining genome integrity and ensuring the normal transcription of genes.Polycomb group(PcG)proteins regulate chromatin states not only by modifying the chromatin,but...The accurate chromatin states are essential for maintaining genome integrity and ensuring the normal transcription of genes.Polycomb group(PcG)proteins regulate chromatin states not only by modifying the chromatin,but also by influencing the chromatin three-dimensional(3D)structure.The core components of Polycomb repressive complex 1(PRC1),B LYMPHOMA MOLONEY MURINE LEUKEMIA VIRUS INSERTION REGION 1 HOMOLOG 1A/B/C(BMI1s),have been reported to maintain the compartment domains(CDs)generally,but the mechanism by which they function remains elusive.Here,we reveal that condensin complexes,whose function are related to chromatin or chromosome,can interact with BMI1s.Removal of condensin I or II also leads to global impairment of CDs.The significantly impaired CDs in bmi1a/b/c and condensin mutants are basically the same and the CDs co-regulated by BMI1s and condensin complexes have higher strength in the wild-type(WT,Col-0)plant,indicating that BMI1s and condensin complexes cooperate to maintain CDs.This regulatory function is parallel to the function of histone modifications deposited by PcG in maintaining CDs,since removal of either condensin I or II does not obviously disrupt the genome-wide level of H3K27me3 and H2AK121ub.Moreover,we discovered that BMI1s and condensin complexes jointly influence the expression of a portion of genes to enable normal plant growth and may maintain the genome integrity under stress conditions.Thus,our work proides a perspective for the gene expression and epigenetic regulatory mechanism of PRC1,in Arabidopsis,in addition to histone modifications.展开更多
Anti-PD-1/PD-L1 immune checkpoint blockade(ICB)therapy has revolutionized clinical cancer treatment,while abnormal PD-L1 or HLA-l expression in patients can significantly impact the therapeutic efficacy.Somatic mutati...Anti-PD-1/PD-L1 immune checkpoint blockade(ICB)therapy has revolutionized clinical cancer treatment,while abnormal PD-L1 or HLA-l expression in patients can significantly impact the therapeutic efficacy.Somatic mutations in cancer cells that modulate these critical regulators are closely associated with tumor progression and ICB response.However,a systematic interpretation of cancer immune-related mutations is stll lacking.Here,we harnessed the ABEmax system to establish a large-scale sgRNA library encompassing approximately 820,000 sgRNAs that target all feasible serine/threonine/tyrosine residues across the human genome,which systematically unveiled thousands of novel mutations that decrease or augment PD-L1 or HLA-I expression.Beyond residues associated with phosphorylation events,our screens also identified functional mutations that affect mRNA or protein stability,DNA binding capacity,protein-protein interactions,and enzymatic catalytic activity,leading to either gene inactivation or activation.Notably,we uncovered certain mutations that concurrently modulate PD-L1 and HLA-I expression,represented by the clinically relevant mutation SETD2_Y1666.We demonstrated that this mutation induces consistent phenotypic effects across multiple cancer cell lines and enhances the efficacy of immunotherapy in different tumor models.Our findings provide an unprecedented resource of functional residues that regulate cancer immunosurveillance,offering valuable guidance for clinical diagnosis,ICB therapy,and the development of innovative drugs for cancer treatment.展开更多
RNA molecules are widely regarded as one of the most ancient molecular forms of life.In 1960s,Francis Crick,Leslie Orgel and Carl R.Woese proposed that RNAs might be the original biomolecule,a concept that later cryst...RNA molecules are widely regarded as one of the most ancient molecular forms of life.In 1960s,Francis Crick,Leslie Orgel and Carl R.Woese proposed that RNAs might be the original biomolecule,a concept that later crystallized into the“Primordial RNA World”theory.The discovery of catalytic RNAs,called ribozymes,in the 1980s provided compelling experimental support for this idea.Over billions of years of evolution,from simple to complex organisms,RNAs have maintained their central roles in both the expression and the regulation of genetic information.展开更多
The plant microbiome plays a vital role in crop health,resilience,and productivity,orchestrating nutrient cycling,disease resistance,and stress tolerance(Compant et al.,2025).Recently,Ge and Wang proposed two strategi...The plant microbiome plays a vital role in crop health,resilience,and productivity,orchestrating nutrient cycling,disease resistance,and stress tolerance(Compant et al.,2025).Recently,Ge and Wang proposed two strategies to manipulate these microbial communities by plant breeding and designing inoculants(Ge and Wang,2025).展开更多
基金supported by the Major Program of the National Natural Science Foundation of China(No.82293630)the Peking University Medicine Fund for the world’s leading discipline or discipline cluster development(No.71003Y3035)+1 种基金the National Key Research and Development Program of China(Nos.2022YFA0103300,2017YFA0104500,and 2016YFC0901603)the State Key Laboratory of Gene Function and Modulation Research and the Beijing Advanced Innovation Center for Genomics(ICG)at Peking University.
文摘Human leukocyte antigen(HLA)disparity between donors and recipients is a key determinant triggering intense alloreactivity,leading to a lethal complication,namely,acute graft-versus-host disease(aGVHD),after allogeneic transplantation.Moreover,aGVHD remains a cause of mortality after HLA-matched allogeneic transplantation.Protocols for HLA-haploidentical hematopoietic cell transplantation(haploHCT)have been established successfully and widely applied,further highlighting the urgency of performing panoramic screening of non-HLA variations correlated with aGVHD.On the basis of our time-consecutive large haploHCT cohort(with a homogenous discovery set and an extended confirmatory set),we first delineated the genetic landscape of 1366 samples to quantitatively model aGVHD risk by assessing the contributions of HLA and non-HLA genes together with clinical factors.In addition to identifying multiple loss-of-function(LoF)risk variations in non-HLA coding genes,our data-driven study revealed that non-HLA genetic variations,independent of HLA disparity,contributed the most to the occurrence of aGVHD.This unexpected major effect was verified in an independent cohort that received HLA-identical sibling HCT.Subsequent functional experiments further revealed the roles of a representative non-HLA LoF gene and LoF gene pair in regulating the alloreactivity of primary human T cells.Our findings highlight the importance of non-HLA genetic risk in the new era of transplantation and propose a new direction to explore the immunogenetic mechanism of alloreactivity and to optimize donor selection strategies for allogeneic transplantation.
基金supported by Grant 32370612(Yue Zhou)from the National Natural Science Foundation of China,Biological Breeding-National Science and Technology Major Project(2023ZD04073)Grant JCTD-2022-06(Yue Zhou)supported by CAS Youth Interdisciplinary Team,startup funds from the State Key Laboratory of Gene Function and Modulation Research,the School of Advanced Agricultural Sciencesthe Peking-Tsinghua Center for Life Sciences at Peking University(Yue Zhou).
文摘The accurate chromatin states are essential for maintaining genome integrity and ensuring the normal transcription of genes.Polycomb group(PcG)proteins regulate chromatin states not only by modifying the chromatin,but also by influencing the chromatin three-dimensional(3D)structure.The core components of Polycomb repressive complex 1(PRC1),B LYMPHOMA MOLONEY MURINE LEUKEMIA VIRUS INSERTION REGION 1 HOMOLOG 1A/B/C(BMI1s),have been reported to maintain the compartment domains(CDs)generally,but the mechanism by which they function remains elusive.Here,we reveal that condensin complexes,whose function are related to chromatin or chromosome,can interact with BMI1s.Removal of condensin I or II also leads to global impairment of CDs.The significantly impaired CDs in bmi1a/b/c and condensin mutants are basically the same and the CDs co-regulated by BMI1s and condensin complexes have higher strength in the wild-type(WT,Col-0)plant,indicating that BMI1s and condensin complexes cooperate to maintain CDs.This regulatory function is parallel to the function of histone modifications deposited by PcG in maintaining CDs,since removal of either condensin I or II does not obviously disrupt the genome-wide level of H3K27me3 and H2AK121ub.Moreover,we discovered that BMI1s and condensin complexes jointly influence the expression of a portion of genes to enable normal plant growth and may maintain the genome integrity under stress conditions.Thus,our work proides a perspective for the gene expression and epigenetic regulatory mechanism of PRC1,in Arabidopsis,in addition to histone modifications.
基金supported by funds from Changping Laboratory,the National Natural Science Foundation of China(NSFC 31930016)Beijing Advanced Innovation Center for Genomics at Peking University,and the Peking-Tsinghua Center for Life Sciences(to W.W.)+2 种基金Additional support was provided by the China Postdoctoral Science Foundation(2020M670031,to Y.L2020M670053,to Y-S.L.)the Taishan Scholarship(tsqn202312362,to Y-S.L.).
文摘Anti-PD-1/PD-L1 immune checkpoint blockade(ICB)therapy has revolutionized clinical cancer treatment,while abnormal PD-L1 or HLA-l expression in patients can significantly impact the therapeutic efficacy.Somatic mutations in cancer cells that modulate these critical regulators are closely associated with tumor progression and ICB response.However,a systematic interpretation of cancer immune-related mutations is stll lacking.Here,we harnessed the ABEmax system to establish a large-scale sgRNA library encompassing approximately 820,000 sgRNAs that target all feasible serine/threonine/tyrosine residues across the human genome,which systematically unveiled thousands of novel mutations that decrease or augment PD-L1 or HLA-I expression.Beyond residues associated with phosphorylation events,our screens also identified functional mutations that affect mRNA or protein stability,DNA binding capacity,protein-protein interactions,and enzymatic catalytic activity,leading to either gene inactivation or activation.Notably,we uncovered certain mutations that concurrently modulate PD-L1 and HLA-I expression,represented by the clinically relevant mutation SETD2_Y1666.We demonstrated that this mutation induces consistent phenotypic effects across multiple cancer cell lines and enhances the efficacy of immunotherapy in different tumor models.Our findings provide an unprecedented resource of functional residues that regulate cancer immunosurveillance,offering valuable guidance for clinical diagnosis,ICB therapy,and the development of innovative drugs for cancer treatment.
文摘RNA molecules are widely regarded as one of the most ancient molecular forms of life.In 1960s,Francis Crick,Leslie Orgel and Carl R.Woese proposed that RNAs might be the original biomolecule,a concept that later crystallized into the“Primordial RNA World”theory.The discovery of catalytic RNAs,called ribozymes,in the 1980s provided compelling experimental support for this idea.Over billions of years of evolution,from simple to complex organisms,RNAs have maintained their central roles in both the expression and the regulation of genetic information.
基金funded by the National Natural Science Foundation of China(32472502 and 32230089)the Fundamental Research Funds for the Central Universities(KJYQ2025050).
文摘The plant microbiome plays a vital role in crop health,resilience,and productivity,orchestrating nutrient cycling,disease resistance,and stress tolerance(Compant et al.,2025).Recently,Ge and Wang proposed two strategies to manipulate these microbial communities by plant breeding and designing inoculants(Ge and Wang,2025).
