Background:Nuclear receptor-binding SET domain 2(NSD2)is a histone methyltrans-ferase,that catalyzes dimethylation of lysine 36 of histone 3(H3K36me2)and is asso-ciated with active transcription of a series of genes.N...Background:Nuclear receptor-binding SET domain 2(NSD2)is a histone methyltrans-ferase,that catalyzes dimethylation of lysine 36 of histone 3(H3K36me2)and is asso-ciated with active transcription of a series of genes.NSD2 is overexpressed in multiple types of solid human tumors and has been proven to be related to unfavorable prog-nosis in several types of tumors.Methods:We established a mouse model in which the NSD2 gene was conditionally knocked out in intestinal epithelial cells.We used azoxymethane and dextran sodium sulfate to chemically induce murine colorectal cancer.The development of colorectal tumors were investigated using post-necropsy quantification,immunohistochemistry,and enzyme-linked immunosorbent assay(ELISA).Results:Compared with wild-type(WT)control mice,NSD2^(fl/fl)-Vil1-Cre mice exhib-ited significantly decreased tumor numbers,histopathological changes,and cytokine expression in colorectal tumors.Conclusions:Conditional knockout of NSD2 in intestinal epithelial cells significantly inhibits colorectal cancer progression.展开更多
自然界中存在对家蚕二分浓核病毒(Bombyx mori Bidensovirus, BmBDV)不敏感的家蚕,对病毒的抗性由家蚕缺失基因+nsd2决定,以该基因为研究对象展开研究。本文利用家蚕中肠cDNA为模版,通过PCR分别扩增出在对BmBDV敏感家蚕和不敏感家蚕中...自然界中存在对家蚕二分浓核病毒(Bombyx mori Bidensovirus, BmBDV)不敏感的家蚕,对病毒的抗性由家蚕缺失基因+nsd2决定,以该基因为研究对象展开研究。本文利用家蚕中肠cDNA为模版,通过PCR分别扩增出在对BmBDV敏感家蚕和不敏感家蚕中均表达的+nsd2基因序列中的3部分截短片段,以及仅在对BmBDV敏感家蚕中表达的+nsd2基因序列的截短片段,测序后将扩增出的片段分别连接至pET-30a原核表达载体。异丙基-β-D-硫代半乳糖苷诱导融合蛋白表达,对诱导得出的带有6*His标签的融合蛋白进行SDS-PAGE电泳和Western blot分析。将得到的蛋白纯化后与弗氏佐剂按一定比例混合,充分乳化后对小鼠进行皮下注射免疫。利用制得的抗血清对原核表达产物和家蚕中肠组织蛋白进行免疫印迹分析。SDS-PAGE电泳和Western blot分析证明成功构建带有6*His标签和不同截短蛋白的原核表达载体,获得对应的2种重组融合蛋白,利用该蛋白制备2种多克隆抗体,制得的抗体可分别对敏感型家蚕和不敏感家蚕进行分析检测,该抗体还可验证+NSD2蛋白在家蚕中肠内的特异性表达。本研究成功实现2种不同截短蛋白的表达,利用截短+NSD2蛋白制备的2种多克隆抗体可分别特异性检测+NSD2完整型蛋白和NSD2缺失型蛋白,为后续对+NSD2蛋白跨膜域缺失后的功能探究奠定了基础。展开更多
Stem cells play a crucial role in maintaining tissue regenerative capacity and homeostasis.However,mechanisms associated with stem cell senescence require further investigation.In this study,we conducted a proteomic a...Stem cells play a crucial role in maintaining tissue regenerative capacity and homeostasis.However,mechanisms associated with stem cell senescence require further investigation.In this study,we conducted a proteomic analysis of human dental pulp stem cells(HDPSCs)obtained from individuals of various ages.Our findings showed that the expression of NUP62 was decreased in aged HDPSCs.We discovered that NUP62 alleviated senescence-associated phenotypes and enhanced differentiation potential both in vitro and in vivo.Conversely,the knocking down of NUP62 expression aggravated the senescence-associated phenotypes and impaired the proliferation and migration capacity of HDPSCs.Through RNA-sequence and decoding the epigenomic landscapes remodeled induced by NUP62 overexpression,we found that NUP62 helps alleviate senescence in HDPSCs by enhancing the nuclear transport of the transcription factor E2F1.This,in turn,stimulates the transcription of the epigenetic enzyme NSD2.Finally,the overexpression of NUP62 influences the H3K36me2 and H3K36me3 modifications of anti-aging genes(HMGA1,HMGA2,and SIRT6).Our results demonstrated that NUP62 regulates the fate of HDPSCs via NSD2-dependent epigenetic reprogramming.展开更多
组蛋白的修饰通过调节染色质结构的疏密程度从而影响基因转录等与DNA有关的生物学功能。NSD蛋白家族(nuclear receptor binding SET domain proteins)(包括NSD1-3)是一组与肿瘤发生相关的组蛋白甲基化转移酶,其中又以NSD2与肿瘤的关系...组蛋白的修饰通过调节染色质结构的疏密程度从而影响基因转录等与DNA有关的生物学功能。NSD蛋白家族(nuclear receptor binding SET domain proteins)(包括NSD1-3)是一组与肿瘤发生相关的组蛋白甲基化转移酶,其中又以NSD2与肿瘤的关系最为密切。近年来的研究发现,NSD2在多发性骨髓瘤、神经母细胞瘤及肝癌等多种肿瘤中高表达,并且相关病人的预后较差。NSD2呈现多种原癌基因的特征:NSD2高表达促进细胞增殖、克隆形成、侵袭能力增强以及肿瘤移植物的生长等。然而,NSD1与NSD3虽然可以与核孔蛋白98 k Da(nucleoporin 98 k Da,NUP98)形成融合蛋白,在部分急性髓性白血病中有致瘤作用,但是它们本身却具有抑癌基因的特点。该文就NSD蛋白家族的最新研究进展作一综述,阐述了NSD蛋白家族在肿瘤发生发展中的作用及潜在的应用前景。展开更多
基金supported by the National Key Research and Development Program of China (2022YFF0710705)the Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences (2021-I2M-1-0 13)+2 种基金funding support from the Special Research Fund for Central UniversitiesPeking Union Medical College (3332022182)the 111 Project (B20095)
文摘Background:Nuclear receptor-binding SET domain 2(NSD2)is a histone methyltrans-ferase,that catalyzes dimethylation of lysine 36 of histone 3(H3K36me2)and is asso-ciated with active transcription of a series of genes.NSD2 is overexpressed in multiple types of solid human tumors and has been proven to be related to unfavorable prog-nosis in several types of tumors.Methods:We established a mouse model in which the NSD2 gene was conditionally knocked out in intestinal epithelial cells.We used azoxymethane and dextran sodium sulfate to chemically induce murine colorectal cancer.The development of colorectal tumors were investigated using post-necropsy quantification,immunohistochemistry,and enzyme-linked immunosorbent assay(ELISA).Results:Compared with wild-type(WT)control mice,NSD2^(fl/fl)-Vil1-Cre mice exhib-ited significantly decreased tumor numbers,histopathological changes,and cytokine expression in colorectal tumors.Conclusions:Conditional knockout of NSD2 in intestinal epithelial cells significantly inhibits colorectal cancer progression.
基金supported by the National Natural Science Foundation of China(32171347)the Foundation of Leading Talents from Shanghai Health Commission(2022XD038)+1 种基金Training Program for Research Physicians in Innovation,the Funda-mental Research Funds for the Central Universities(YG2023QNA23)Transforma-tion from shanghai hospital development center(SHDC2022CRD002).
文摘Stem cells play a crucial role in maintaining tissue regenerative capacity and homeostasis.However,mechanisms associated with stem cell senescence require further investigation.In this study,we conducted a proteomic analysis of human dental pulp stem cells(HDPSCs)obtained from individuals of various ages.Our findings showed that the expression of NUP62 was decreased in aged HDPSCs.We discovered that NUP62 alleviated senescence-associated phenotypes and enhanced differentiation potential both in vitro and in vivo.Conversely,the knocking down of NUP62 expression aggravated the senescence-associated phenotypes and impaired the proliferation and migration capacity of HDPSCs.Through RNA-sequence and decoding the epigenomic landscapes remodeled induced by NUP62 overexpression,we found that NUP62 helps alleviate senescence in HDPSCs by enhancing the nuclear transport of the transcription factor E2F1.This,in turn,stimulates the transcription of the epigenetic enzyme NSD2.Finally,the overexpression of NUP62 influences the H3K36me2 and H3K36me3 modifications of anti-aging genes(HMGA1,HMGA2,and SIRT6).Our results demonstrated that NUP62 regulates the fate of HDPSCs via NSD2-dependent epigenetic reprogramming.
文摘组蛋白的修饰通过调节染色质结构的疏密程度从而影响基因转录等与DNA有关的生物学功能。NSD蛋白家族(nuclear receptor binding SET domain proteins)(包括NSD1-3)是一组与肿瘤发生相关的组蛋白甲基化转移酶,其中又以NSD2与肿瘤的关系最为密切。近年来的研究发现,NSD2在多发性骨髓瘤、神经母细胞瘤及肝癌等多种肿瘤中高表达,并且相关病人的预后较差。NSD2呈现多种原癌基因的特征:NSD2高表达促进细胞增殖、克隆形成、侵袭能力增强以及肿瘤移植物的生长等。然而,NSD1与NSD3虽然可以与核孔蛋白98 k Da(nucleoporin 98 k Da,NUP98)形成融合蛋白,在部分急性髓性白血病中有致瘤作用,但是它们本身却具有抑癌基因的特点。该文就NSD蛋白家族的最新研究进展作一综述,阐述了NSD蛋白家族在肿瘤发生发展中的作用及潜在的应用前景。
