目的探讨H3.3G34W、p63及SATB2在骨巨细胞瘤(giant cell tumor of bone,GCTB)中的表达情况及其联合应用对GCTB的诊断作用和价值。方法收集西安交通大学附属红会医院病理科2020年至2022年诊断的54例GCTB、83例非骨巨细胞瘤(non-giant cel...目的探讨H3.3G34W、p63及SATB2在骨巨细胞瘤(giant cell tumor of bone,GCTB)中的表达情况及其联合应用对GCTB的诊断作用和价值。方法收集西安交通大学附属红会医院病理科2020年至2022年诊断的54例GCTB、83例非骨巨细胞瘤(non-giant cell tumor of bone,NGCTB)(包含14例动脉瘤样骨囊肿、16例软骨母细胞瘤和53例非骨化性纤维瘤)患者的样本和病历资料,采用免疫组织化学EliVision法检测H3.3G34W、p63及SATB2的表达情况。通过χ^(2)检验判断H3.3G34W、p63及SATB2的阳性率在各组间是否存在统计学差异;通过Logistic回归分析建立包括H3.3G34W、p63及SATB2的联合诊断模型,通过受试者工作特征(ROC)曲线分析评价模型的诊断价值。结果H3.3G34W、p63及SATB2在GCTB组中阳性率分别为81.5%、90.7%、92.6%;在NGCTB组中阳性率分别为2.4%、28.9%、62.7%。与NGCTB组相比,GCTB组患者年龄显著较大[(41.222±14.849)vs.(16.566±9.439);P<0.001],女性比男性患病率更高(51.9%vs.48.1%,P<0.001)。与NGCTB组相比,GCTB组中H3.3G34W(81.5%vs.2.4%,P<0.001);p63(90.7%vs.28.9%,P<0.001)和SATB2(92.6%vs.62.7%,P<0.001)的阳性率更高。单因素Logistic回归分析构建单因素预测模型,同时行ROC曲线分析,表明年龄(AUC=92.9%,P<0.001)、性别(AUC=64.5%,P=0.004)、H3.3G34W阳性率(AUC=89.5%,P<0.001)、p63阳性率(AUC=80.9%,P<0.001)、SATB2阳性率(AUC=65.0%,P=0.003)是GCTB诊断的独立预测因素。进一步的多因素Logistic回归分析构建混合预测模型,并行ROC曲线分析,发现混合模型展现出比单因素模型更好的预测价值(AUC=98.4%,P<0.001)。结论H3.3G34W、p63及SATB2是有效诊断GCTB的分子标记物,且三者联合应用更能提高GCTB的诊断预测效能。展开更多
The conserved histone variant H3.3 plays pivotal roles in heterochromatin formation and retrotransposon silencing.However,the molecular mechanism underlying H3.3-primed heterochromatin regulation remains elusive.Here,...The conserved histone variant H3.3 plays pivotal roles in heterochromatin formation and retrotransposon silencing.However,the molecular mechanism underlying H3.3-primed heterochromatin regulation remains elusive.Here,we demonstrate that H3.3-specific Ser31 phosphorylation and Lys27 trimethylation synergistically promote H3K9me3-heterochromatin formation.Mechanistically,polycomb protein chromobox homolog 7(CBX7)preferentially binds Ser31-phosphorylated H3.3K27me3 nucleosomes and then recruits KRAB-associated protein 1(KAP1),which may further engage the histone lysine 9 methyltransferase to establish H3K9me3-associated heterochromatin.Remarkably,H3K9me3 is significantly impaired when the H3.3–CBX7 interaction is disrupted,accompanied by the activation of retrotransposons.Moreover,during X-chromosome inactivation(XCI),H3K9me2/3 fails to accumulate at the inactive X(Xi)when blocking the H3.3–CBX7–KAP1 axis.Taken together,our results reveal a novel molecular mechanism by which H3.3 Ser31 phosphorylation(H3.3Ser31p)facilitates H3K9me3-heterochromatin formation during retrotransposon silencing and XCI via the H3.3K27me3–CBX7–KAP1 axis.展开更多
Histones are the main protein components of eukaryotic chromatin. Histone variants and histone modifications modulate chromatin structure, ensuring the precise operation of cellular processes associated with genomic D...Histones are the main protein components of eukaryotic chromatin. Histone variants and histone modifications modulate chromatin structure, ensuring the precise operation of cellular processes associated with genomic DNA. H3.3, an ancient and conserved H3 variant, differs from its canonical H3 counterpart by only five amino acids, yet it plays essential and specific roles in gene transcription, DNA repair and in maintaining genome integrity. Here, we review the most recent insights into the functions of histone H3.3, and the involvement of its mutant forms in human diseases.展开更多
Histone point mutations,including missense mutations on histone H3 at positions 27(K27M),34(G34R/V,G34W,G34L)and 36(K36M),were identified as potential cancer driver mutations.H3.3G34R/V mutations account for pediatric...Histone point mutations,including missense mutations on histone H3 at positions 27(K27M),34(G34R/V,G34W,G34L)and 36(K36M),were identified as potential cancer driver mutations.H3.3G34R/V mutations account for pediatric glioblastomas(GBM).RACK7(also known as ZMYND8,PRKCBP1)was recently reported to specifically bind H3.3G34R through its PHD(plant homedomain)domain(PHDRACK7)in vitro and in H3.3G34R pediatric glioblastoma cells,playing key roles in H3.3G34R-mediated gene transcription.Herein,we provided both biochemical and NMR structural evidences that PHDRACK7 recognized histone H3.3G34R mutant via a mechanism distinet from all other reported PHD domains.Except the reported residue D104,two new sites D108 and L121 of PHD^(RACK7) were found necessary for the interactions between PHD^(RACK7) and histone H3.3G34R peptide.Our results provided a potential molecular basis for pediatric GBM driven by the H3.3G34R mutation.展开更多
骨巨细胞瘤 (giant cell tumor of bone,GCTB)是发生在骨关节骺端的一种常见的交界性肿瘤,具有局部复发性以及罕见远处转移可能,很少发生恶性变。骨巨细胞瘤中的恶性肿瘤 (malignancy in giant cell tumor of bone,MGCTB),也就是过去称...骨巨细胞瘤 (giant cell tumor of bone,GCTB)是发生在骨关节骺端的一种常见的交界性肿瘤,具有局部复发性以及罕见远处转移可能,很少发生恶性变。骨巨细胞瘤中的恶性肿瘤 (malignancy in giant cell tumor of bone,MGCTB),也就是过去称谓的恶性骨巨细胞瘤,在骨巨细胞瘤中含有高级别肉瘤成分。依据最初诊断时就证实同时存在高级别肉瘤成分.展开更多
文摘目的探讨H3.3G34W、p63及SATB2在骨巨细胞瘤(giant cell tumor of bone,GCTB)中的表达情况及其联合应用对GCTB的诊断作用和价值。方法收集西安交通大学附属红会医院病理科2020年至2022年诊断的54例GCTB、83例非骨巨细胞瘤(non-giant cell tumor of bone,NGCTB)(包含14例动脉瘤样骨囊肿、16例软骨母细胞瘤和53例非骨化性纤维瘤)患者的样本和病历资料,采用免疫组织化学EliVision法检测H3.3G34W、p63及SATB2的表达情况。通过χ^(2)检验判断H3.3G34W、p63及SATB2的阳性率在各组间是否存在统计学差异;通过Logistic回归分析建立包括H3.3G34W、p63及SATB2的联合诊断模型,通过受试者工作特征(ROC)曲线分析评价模型的诊断价值。结果H3.3G34W、p63及SATB2在GCTB组中阳性率分别为81.5%、90.7%、92.6%;在NGCTB组中阳性率分别为2.4%、28.9%、62.7%。与NGCTB组相比,GCTB组患者年龄显著较大[(41.222±14.849)vs.(16.566±9.439);P<0.001],女性比男性患病率更高(51.9%vs.48.1%,P<0.001)。与NGCTB组相比,GCTB组中H3.3G34W(81.5%vs.2.4%,P<0.001);p63(90.7%vs.28.9%,P<0.001)和SATB2(92.6%vs.62.7%,P<0.001)的阳性率更高。单因素Logistic回归分析构建单因素预测模型,同时行ROC曲线分析,表明年龄(AUC=92.9%,P<0.001)、性别(AUC=64.5%,P=0.004)、H3.3G34W阳性率(AUC=89.5%,P<0.001)、p63阳性率(AUC=80.9%,P<0.001)、SATB2阳性率(AUC=65.0%,P=0.003)是GCTB诊断的独立预测因素。进一步的多因素Logistic回归分析构建混合预测模型,并行ROC曲线分析,发现混合模型展现出比单因素模型更好的预测价值(AUC=98.4%,P<0.001)。结论H3.3G34W、p63及SATB2是有效诊断GCTB的分子标记物,且三者联合应用更能提高GCTB的诊断预测效能。
基金supported by the Ministry of Science and Technology of China(2023YFA0913402)the National Natural Science Foundation of China(32230020,32571493,32171186,32270614,32270581,and 32370645)+3 种基金Basic Research Program Based on Major Scientific Infrastructures,CAS(JZHKYPT-2021-05)supported by the Beijing Municipal Science and Technology Committee(Z221100007022001)the Fundamental Research Funds for the Central Universities(2042022dx0003)supported by the New Cornerstone Science Foundation.
文摘The conserved histone variant H3.3 plays pivotal roles in heterochromatin formation and retrotransposon silencing.However,the molecular mechanism underlying H3.3-primed heterochromatin regulation remains elusive.Here,we demonstrate that H3.3-specific Ser31 phosphorylation and Lys27 trimethylation synergistically promote H3K9me3-heterochromatin formation.Mechanistically,polycomb protein chromobox homolog 7(CBX7)preferentially binds Ser31-phosphorylated H3.3K27me3 nucleosomes and then recruits KRAB-associated protein 1(KAP1),which may further engage the histone lysine 9 methyltransferase to establish H3K9me3-associated heterochromatin.Remarkably,H3K9me3 is significantly impaired when the H3.3–CBX7 interaction is disrupted,accompanied by the activation of retrotransposons.Moreover,during X-chromosome inactivation(XCI),H3K9me2/3 fails to accumulate at the inactive X(Xi)when blocking the H3.3–CBX7–KAP1 axis.Taken together,our results reveal a novel molecular mechanism by which H3.3 Ser31 phosphorylation(H3.3Ser31p)facilitates H3K9me3-heterochromatin formation during retrotransposon silencing and XCI via the H3.3K27me3–CBX7–KAP1 axis.
基金supported by the National Natural Science Foundation of China(91219202)to Guohong Li.the Ministry of Science and Technology of China(2015CB856200+2 种基金2011CB966300)the Chinese Academy of Sciences(CAS)Strategic Priority Research Program(XDA01010304)the National Natural Science Foundation of China(31301047)to Chaoyang Xiong
文摘Histones are the main protein components of eukaryotic chromatin. Histone variants and histone modifications modulate chromatin structure, ensuring the precise operation of cellular processes associated with genomic DNA. H3.3, an ancient and conserved H3 variant, differs from its canonical H3 counterpart by only five amino acids, yet it plays essential and specific roles in gene transcription, DNA repair and in maintaining genome integrity. Here, we review the most recent insights into the functions of histone H3.3, and the involvement of its mutant forms in human diseases.
基金supported by the National Program on the Key Basic Research Project of China(Nos.2017YFE0108200,2018YFA0108700,2016YFA0502302 and 2016YFA0500700)by NSFC(Nos.21807105,91753119,21977110,31571318,21778065 and 31771450)+1 种基金by the Strategic Priority Research Program,CAS(No.XDB 20000000)by Center for Excellence in Molecular Synthesis,CAS(No.FZHCZY020600)。
文摘Histone point mutations,including missense mutations on histone H3 at positions 27(K27M),34(G34R/V,G34W,G34L)and 36(K36M),were identified as potential cancer driver mutations.H3.3G34R/V mutations account for pediatric glioblastomas(GBM).RACK7(also known as ZMYND8,PRKCBP1)was recently reported to specifically bind H3.3G34R through its PHD(plant homedomain)domain(PHDRACK7)in vitro and in H3.3G34R pediatric glioblastoma cells,playing key roles in H3.3G34R-mediated gene transcription.Herein,we provided both biochemical and NMR structural evidences that PHDRACK7 recognized histone H3.3G34R mutant via a mechanism distinet from all other reported PHD domains.Except the reported residue D104,two new sites D108 and L121 of PHD^(RACK7) were found necessary for the interactions between PHD^(RACK7) and histone H3.3G34R peptide.Our results provided a potential molecular basis for pediatric GBM driven by the H3.3G34R mutation.
文摘骨巨细胞瘤 (giant cell tumor of bone,GCTB)是发生在骨关节骺端的一种常见的交界性肿瘤,具有局部复发性以及罕见远处转移可能,很少发生恶性变。骨巨细胞瘤中的恶性肿瘤 (malignancy in giant cell tumor of bone,MGCTB),也就是过去称谓的恶性骨巨细胞瘤,在骨巨细胞瘤中含有高级别肉瘤成分。依据最初诊断时就证实同时存在高级别肉瘤成分.
