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Science Bulletin 2024年第8期69卷 1122-1136页

作者：朱子健何美娜张拓赵庭秦韶刚高萌王文基郑文影陈子琦刘龙萍郝明周波张华王建斌王凤超夏国良王超 State Key Laboratory of Farm Animal Biotech Breeding College of Biological SciencesChina Agricultural UniversityBeijing 100193China College of Basic Medicine Guizhou Medical UniversityGuiyang 550025China Guizhou Provincial Key Laboratory of Pathogenesis and Drug Research on Common Chronic Diseases Department of PhysiologyCollege of Basic MedicineGuizhou Medical UniversityGuiyang 550025China School of Life Sciences Taizhou UniversityTaizhou 318000China School of Life Sciences Tsinghua UniversityBeijing 100084China Transgenic Animal Center National Institute of Biological SciencesBeijing 102206China Key Laboratory of Ministry of Education for Conservation and Utilization of Special Biological Resources in the Western China College of Life ScienceNingxia UniversityYinchuan 750021China

In a growing follicle,the survival and maturation of the oocyte largely depend on support from somatic cells to facilitate FSH-induced mutual signaling and chemical communication.Although apoptosis and autophagy in somatic cells are involved in the process of FSH-induced follicular development,the underlying mechanisms require substantial study.According to our study,along with FSH-induced antral follicles(AFs)formation,both lysine-specific demethylase 1(lsd1)protein levels and autophagy increased simultaneously in granulosa cells(GCs)in a time-dependent manner,we therefore evaluated the importance of lsd upon facilitating the formation of AFs correlated to autophagy in GCs.Conditional knockout of lsdl in GCs resulted in significantly decreased AF number and subfertility in females,accompanied by marked suppression of the autophagy in GCs.On the one hand,depletion of lsd1 resulted in accumulation of Wilms tumor 1 homolog(WT1),at both the protein and mRNA levels.WT1 prevented the expression of FSH receptor(Fshr)in GCs and thus reduced the responsiveness of the secondary follicles to FSH induction.On the other hand,depletion of lsd1 resulted in suppressed level of autophagy by upregulation of ATG16L2 in GCs.We finally approved that lsd1 contributed to these sequential activities in GCs through its H3K4me2 demethylase activity.Therefore,the importance of lsd1 in GCs is attributable to its roles in both accelerating autophagy and suppressing WT1 expression to ensure the responsiveness of GCs to FSH during AFs formation.

关键词： lsd1 Autophagy H3K4me2 WT1 Follicle formation Follicle stimulating hormone

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赖氨酸特异性去甲基化酶1（lsd1）抑制剂的研究进展

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中国药科大学学报 2024年

作者：张晓梦付金洋何雅楠弓建红杜锟吴亚支燕乐河南中医药大学药学院

赖氨酸特异性去甲基化酶1（lsd1）是一种黄素腺嘌呤二核苷酸（FAD）依赖的单胺氧化酶。研究证实，lsd1的异常表达与肿瘤的转移和增殖密切相关，是目前肿瘤靶向治疗的重要靶点之一。另外，lsd1还参与神经退行性疾病、心血管疾病、炎症反... 详细信息

赖氨酸特异性去甲基化酶1（lsd1）是一种黄素腺嘌呤二核苷酸（FAD）依赖的单胺氧化酶。研究证实，lsd1的异常表达与肿瘤的转移和增殖密切相关，是目前肿瘤靶向治疗的重要靶点之一。另外，lsd1还参与神经退行性疾病、心血管疾病、炎症反应等多种疾病的发生发展。目前，已经有多个抑制剂进入临床研究阶段。本文对lsd1的结构、作用机制以及lsd1抑制剂的研究进展作简要介绍，为设计开发新型lsd1抑制剂提供参考。

关键词： lsd1 肿瘤去甲基化酶抑制剂临床研究

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lsd1 is required for euchromatic origin firing and replication timing

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Signal Transduction and Targeted Therapy 2022年第5期7卷 1703-1718页

作者： Yue Wang Yunchao Huang Edith Cheng Xinhua Liu Yu Zhang Jianguo Yang Jordan T.F.Young Grant W.Brown Xiaohan Yang Yongfeng Shang Department of Biochemistry and Molecular Biology School of Basic Medical SciencesPeking University Health Science CenterBeijing 100191China Department of Biochemistry and Molecular Biology School of Basic Medical SciencesHangzhou Normal UniversityHangzhou 311121China Department of Biochemistry and Molecular Biology School of Basic Medical SciencesCapital Medical UniversityBeijing 100069China Department of Biochemistry and Donnelly Centre University of TorontoTorontoON M5S 1A8Canada Lunenfeld-Tanenbaum Research Institute Mount Sinai Hospital600 University Ave.TorontoON M5G 1×5Canada

The chromatin-based rule governing the selection and activation of replication origins remains to be elucidated.It is believed that DNA replication initiates from open chromatin domains;thus,replication origins reside in open and active chromatin.However,we report here that lysine-specific demethylase 1(lsd1),which biochemically catalyzes H3K4me1/2 demethylation favoring chromatin condensation,interacts with the DNA replication machinery in human cells.We find that lsd1 level peaks in early S phase.

关键词： origin lsd1 replication

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Counteracting lineage-specific transcription factor network finely tunes lung adeno-to-squamous transdifferentiation through remodeling tumor immune microenvironment

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National Science Review 2023年第4期10卷 37-55页

作者： Shijie Tang Yun Xue Zhen Qin Zhaoyuan Fang Yihua Sun Chongzhe Yuan Yunjian Pan Yue Zhao Xinyuan Tong Jian Zhang Hsinyi Huang Yuting Chen Liang Hu Dasong Huang Ruiqi Wang Weiguo Zou Yuan Li Roman K.Thomas Andrea Ventura Kwok-Kin Wong Haiquan Chen Luonan Chen Hongbin Ji Department of Pathology University Hospital Cologne Cancer Biology and Genetics Program Memorial Sloan Kettering Cancer Center Laura and Isaac Perlmutter Cancer Center New York University Langone Medical Center Key Laboratory of Systems Biology Shanghai Institutes for Biological SciencesChinese Academy of Sciences School of Life Science Hangzhou Institute for Advanced StudyUniversity of Chinese Academy of SciencesChinese Academy of Sciences State Key Laboratory of Cell Biology Shanghai Institute of Biochemistry and Cell BiologyCenter for Excellence in Molecular Cell ScienceChinese Academy of Sciences College of Life Sciences University of Chinese Academy of Sciences Zhejiang University-University of Edinburgh Institute Zhejiang University School of Medicine The Second Affiliated Hospital Zhejiang University School of Medicine Department of Thoracic Surgery Fudan University Shanghai Cancer Center Department of Oncology Shanghai Medical CollegeFudan University School of Life Science and Technology Shanghai Tech University Department of Mathematics Shanghai University Department of Translational Genomics Center of Integrated Oncology Cologne-BonnMedical FacultyUniversity of Cologne

Human lung adenosquamous cell carcinoma(LUAS), containing both adenomatous and squamous pathologies, harbors strong plasticity and is significantly associated with poor prognosis. We established an up-to-date comprehensive genomic and transcriptomic landscape of LUAS in 109 Chinese specimens and demonstrated LUAS development via adeno-to-squamous transdifferentiation. Unsupervised transcriptomic clustering and dynamic network biomarker analysis identified an inflammatory subtype as the critical transition stage during LUAS development. Dynamic dysregulation of the counteracting lineage-specific transcription factors(TFs), containing adenomatous TFs NKX2-1 and FOXA2, and squamous TFs TP63 and SOX2, finely tuned the lineage transition via promoting CXCL3/5-mediated neutrophil infiltration. Genomic clustering identified the most malignant subtype featured with STK11-inactivation, and targeting lsd1 through genetic deletion or pharmacological inhibition almost eradicated STK11-deficient lung tumors. These data collectively uncover the comprehensive molecular landscape, oncogenic driver spectrum and therapeutic vulnerability of Chinese LUAS.

关键词： LUAS ALK fusion counteracting TF regulatory network CXCL3/CXCL5 lsd1

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lsd1 inhibition suppresses the growth of clear cell renal cell carcinoma via upregulating P21signaling

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Acta Pharmaceutica Sinica B 2019年第2期9卷 324-334页

作者： Liangsong Zhu Jianfeng Wang Wen Kong Jiwei Huang Baijun Dong Yiran Huang Wei Xue Jin Zhang Department of Urology Ren Ji Hospital School of Medicine Shanghai Jiaotong University

Histone lysine-specific demethylase 1(lsd1) has been implicated in the disease progression of several types of solid tumors. This study provides the first evidence showing that lsd1 overexpression occurred in 62.6%(224/358) of clear cell renal cell carcinomas(ccRCC). lsd1 expression was associated with the progression of ccRCC, as indicated by TNM stage(P ? 0.006), especially tumor stage(P ? 0.017) and lymph node metastasis(P ? 0.030). High lsd1 expression proved to be an independent prognostic factor for poor overall survival(Po0.001) and recurrence-free survival(Po0.001) of ccRCC patients. We further show that lsd1 inhibition by siRNA knockdown or using the small molecule inhibitor SP2509 suppressed the growth of ccRCC in vitro and in vivo. Mechanistically, inhibition of lsd1 decreased the H3 K4 demethylation at the CDKN1 A gene promoter, which was associated with P21 upregulation and cell cycle arrest at G1/S in ccRCC cells. Our findings provide new mechanistic insights into the role of lsd1 in cc RCC and suggest the therapeutic potential of lsd1 inhibitors in ccRCC treatment.

关键词： Clear cell renal cell carcinoma lsd1 Prognosis Proliferation P21

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Development of the triazole-fused pyrimidine derivatives as highly potent and reversible inhibitors of histone lysine specific demethylase1(lsd1/KDM1A)

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Acta Pharmaceutica Sinica B 2019年第4期9卷 794-808页

作者： Zhonghua Li Lina Ding Zhongrui Li Zhizheng Wang Fengzhi Suo Dandan Shen Taoqian Zhao Xudong Sun Junwei Wang Ying Liu Liying Ma Bing Zhao Pengfei Geng Bin Yu Yichao Zheng Hongmin Liu School of Pharmaceutical Sciences Zhengzhou UniversityZhengzhou 450001China State Key Laboratory of Pharmaceutical Biotechnology Nanjing UniversityNanjing 210023China Co-Innovation Center of Henan Province for New Drug R&D and Preclinical Safety Zhengzhou 450001China Key Laboratory of Advanced Drug Preparation Technologies Ministry of Education of ChinaZhengzhou 450001China

Histone lysine specific demethylase 1(lsd1) has been recognized as an important modulator in post-translational process in epigenetics. Dysregulation of lsd1 has been implicated in the development of various cancers. Herein, we report the discovery of the hit compound 8 a(IC50=3.93 μmol/L) and further medicinal chemistry efforts, leading to the generation of compound 15 u(IC50=49 nmol/L, and Ki= 16 nmol/L), which inhibited lsd1 reversibly and competitively with H3 K4 me2, and was selective to lsd1 over MAO-A/B. Docking studies were performed to rationalize the potency ofcompound 15 u. Compound 15 u also showed strong antiproliferative activity against four leukemia cell lines(OCL-AML3, K562, THP-1 and U937) as well as the lymphoma cell line Raji with the IC50 values of 1.79, 1.30, 0.45, 1.22 and 1.40 μmol/L, respectively. In THP-1 cell line, 15 u significantly inhibited colony formation and caused remarkable morphological changes. Compound 15 u induced expression of CD86 and CD11 b in THP-1 cells, confirming its cellular activity and ability of inducing differentiation.The findings further indicate that targeting lsd1 is a promising strategy for AML treatment, the triazolefused pyrimidine derivatives are new scaffolds for the development of lsd1/KDM1 A inhibitors.

关键词： Epigenetic regulation Histone demethylase lsd1 Pyrimidine-triazole Mercapto heterocycles Antiproliferative ability AML treatment Structure–activity relationships(SARs)

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Roles of SET7/9 and lsd1 in the Pathogenesis of Arsenicinduced Hepatocyte Apoptosis

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Journal of Clinical and Translational Hepatology 2021年第3期9卷 364-372页

作者： Bing Han Yi Yang Lei Tang Qin Yang Rujia Xie Department of Pathophysiology College of Basic Medical SciencesGuizhou Medical UniversityGuiyangGuizhouChina Guizhou Provincial Key Laboratory of Pathogenesis and Drug Research on Common Chronic Diseases Guizhou Medical UniversityGuiyangGuizhouChina Medical College of Guizhou University GuiyangGuizhouChina

Background and Aims:Multiple regulatory mechanisms play an important role in arsenic-induced liver injury.To investigate whether histone H3 lysine 4(H3K4)methyltransferase(SET7/9)and histone H3K4 demethyltransferase(lsd1/KDM1A)can regulate endoplasmic reticulum stress(ERS)-related apoptosis by modulating the changes of H3K4 methylations in liver cells treated with arsenic.Methods:Apoptosis,proliferation and cell cycles were quantified by flow cytometry and real-time cell analyzer.The expression of ERS-and epigenetic-related proteins was detected by Western blot analysis.The antisense SET7/9 expression vector and the overexpressed lsd1 plasmid were used for transient transfection of LO_(2) cells.The effects of NaAsO_(2) on the methylation of H3 in the promoter regions of 78 kDa glucose-regulated protein,activating transcription factor 4 and C/EBP-homologous protein were evaluated by chromatin immunoprecipitation assay.Results:The protein expression of lsd1(1.25±0.08 vs.1.77±0.08,p=0.02)was markedly decreased by treatment with 100μM NaAsO_(2),whereas the SET7/9(0.68±0.05 vs.1.10±0.13,p=0.002)expression level was notably increased,which resulted in increased H3K4me1/2(0.93±0.64,1.19±0.22 vs.0.71±0.13,0.84±0.13,p=0.03 and p=0.003).After silencing SET7/9 and overexpressing lsd1 by transfection,apoptosis rate(in percentage:3.26±0.34 vs.7.04±0.42,4.80±0.32 vs.7.52±0.38,p=0.004 and p=0.02)was significantly decreased and proliferation rate was notably increased,which is reversed after inhibiting lsd1(in percentage:9.31±0.40 vs.7.52±0.38,p=0.03).Furthermore,the methylation levels of H3 in the promoter regions of GRP78(20.80±2.40 vs.11.75±2.47,20.46±2.23 vs.14.37±0.91,p=0.03 and p=0.01)and CHOP(48.67±4.04 vs.16.67±7.02,59.33±4.51 vs.20.67±3.06,p=0.004 and p=0.001)were significantly increased in LO_(2) cells exposed to 100μM NaAsO_(2) for 24 h.Conclusions:Histone methyltransferase SET7/9 and histone demethyltransferase lsd1 jointly regulate the changes of H3K4me1/me2 levels in arsenic-induced apoptosis.NaAsO_(2) induces apop

关键词： Arsenic SET7/9 lsd1 H3K4me1/2 ER stress

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HDAC5和lsd1蛋白在胃癌组织中的表达及其预后的关系

HDAC5和LSD1蛋白在胃癌组织中的表达及其预后的关系

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作者：王志成吉林大学

学位级别：硕士

背景:胃癌发生率在世界恶性肿瘤中排名第五,近十年来,随着化疗、放疗、靶向治疗等治疗策略在临床的综合应用,胃癌的五年生存率逐步改善,然而胃癌仍是我国恶性肿瘤相关性死亡的第三大原因。近些年来,靶向治疗和免疫治疗的出现为晚期胃癌... 详细信息

背景:胃癌发生率在世界恶性肿瘤中排名第五,近十年来,随着化疗、放疗、靶向治疗等治疗策略在临床的综合应用,胃癌的五年生存率逐步改善,然而胃癌仍是我国恶性肿瘤相关性死亡的第三大原因。近些年来,靶向治疗和免疫治疗的出现为晚期胃癌患者的治疗提供了全新的思路,例如酪氨酸激酶抑制剂(TKIs)、PD-1/PD-L1单克隆抗体、CTLA-4单克隆抗体、PD-1及CTLA-4单克隆抗体联合疗法等,然而,由于靶点的低效性及低敏感性,并未获得显著的临床获益,例如VEGF抑制剂的单药治疗并未改善胃癌患者的总生存期。因而,探索一种全新的重要且有效的分子标志物,对于提高早期胃癌患者的诊断率、指导中晚期胃癌患者的治疗用药,进而对于预后的改善有深远意义。目的:采用生物信息学方法和免疫组化技术,研究HDAC5、lsd1在胃癌患者的m RNA表达及胃癌患者的临床病理参数与预后之间的关系,为HDAC5、lsd1靶点的临床应用提供实验基础。方法:1.首先我们通过分析在线数据库(Kaplan Meier Plotter数据库、TCGA数据库)中资料,探究HDAC5和lsd1在胃癌组织中的表达及其与胃癌患者预后的关系。2.取2010-2013年于吉林大学第二医院确诊为胃癌的组织标本135例,采用免疫组织化学染色来分析HDAC5和lsd1在胃癌组织中表达的差异。3.采用Kaplan-Meier法及Log-rank检验分析胃癌患者预后,卡方检验分析HDAC5与lsd1表达与临床病理学参数的相关性、Pearson检验分析HDAC5和lsd1表达的相关性。4.利用COX单因素/多因素因素分析HDAC5表达,lsd1表达,HDAC5和lsd1共表达及多种临床病理学参数与胃癌预后的关系。结果:1.我们利用在线数据库分析发现HDAC5及lsd1与胃癌预后呈负相关;HDAC5和lsd1表达呈正相关。2.我们利用免疫组化染色发现HDAC5和lsd1在胃癌组织中高表达,并验证HDAC5和lsd1的表达呈正相关。3.我们利用COX单因素及多因素分析发现HDAC5和lsd1共同高表达可作为胃癌的独立危险因素。结论:1.HDAC5和lsd1在胃癌组织中高表达。2.HDAC5高表达与T分期、lsd1高表达呈正相关。3.HDAC5和lsd1在胃癌组织中共表达为胃癌患者独立危险因素。

关键词：胃癌 HDAC5 lsd1 预后分子标志物

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lsd1调控氯稳态和神经递质兴奋-抑制失衡在大鼠孤独症中的作用研究

LSD1调控氯稳态和神经递质兴奋-抑制失衡在大鼠孤独症中的作用研究

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作者：王凤姣中国医科大学

学位级别：硕士

目的:孤独症谱系障碍是始于儿童早期的神经发育障碍疾病,主要特点是社会交往障碍、重复刻板行为和焦虑行为。目前孤独症的患病率逐年上升,但其发病机制仍不明确。铝用途广泛,与自闭症的发生密切相关。铝是地壳中含量最高的金属元素,广... 详细信息

目的:孤独症谱系障碍是始于儿童早期的神经发育障碍疾病,主要特点是社会交往障碍、重复刻板行为和焦虑行为。目前孤独症的患病率逐年上升,但其发病机制仍不明确。铝用途广泛,与自闭症的发生密切相关。铝是地壳中含量最高的金属元素,广泛存在于日常生活中。婴儿出生后可以通过不同途径接触大量的铝,如婴儿配方奶粉、疫苗接种和肠外营养等。新生儿早期接触有毒金属通常会与ASD相关的异常发育结果有关。研究发现大脑神经传递兴奋抑制(E/I)失衡可能是孤独症行为缺陷的病理基础,但具体调控机制尚不清楚。lsd1是组蛋白赖氨酸特异性去甲基化酶1,最典型的功能就是组蛋白去甲基化作用。此外,已有研究证实lsd1抑制剂TAK-418通过抑制lsd1酶活性可以促进Ucp2 mRNA表达,进而改善神经发育障碍模型中的孤独症行为缺陷,但其具体的机制仍有待阐明。本研究为了更好地模拟出生后早期孤独症的发生情况,拟使用铝联合VPA和LPS构建新型孤独症大鼠模型,检测lsd1调控大鼠孤独症氯稳态和神经传递兴奋抑制失衡相关指标的变化,进一步完善E/I失衡与ASD之间的调控关系,明确lsd1在ASD发病中的作用及可能机制,为ASD的病理机制研究提供重要实验依据和线索。方法:通过孕期给予丙戊酸钠(VPA)或脂多糖(LPS),出生后早期注射铝,建立新型孤独症模型,观察仔鼠生长发育情况、一般行为和神经行为表现;采用HE染色法评估脑组织病理损伤情况;免疫荧光法检测仔鼠NSE水平,评估神经元数目改变;采用ELISA法测定lsd1酶活性、GABA和Glu水平;试剂盒法检测GSH、ATP水平和SOD活性,评价仔鼠氧化损伤情况;蛋白印迹法检测GABRG2、KCC2、NKCC1和UCP2蛋白水平;实时定量PCR法检测Ucp2 mRNA水平;使用免疫荧光法检测GABRG2蛋白表达水平,并分析GABRG2和Gephyrin的共定位;使用MQAE成像法评估氯离子浓度变化,并使用Image J进行定量分析。使用lsd1抑制剂TAK-418抑制lsd1酶活性,并观察仔鼠一系列行为改变和生理生化指标的变化。结果:模型建立。1.生长发育。铝联合丙戊酸钠或脂多糖构建的孤独症动物模型比单独丙戊酸钠或脂多糖建模表现出更加明显的鼠尾弯折、短尾等生长发育畸形。2.一般行为发育。铝联合丙戊酸钠或脂多糖构建的动物模型表现为空中翻正实验、游泳实验、听觉惊愕实验和触须定位实验中达标时间显著延长;在平板翻正实验、负趋地性实验和悬崖回避实验中完成检测耗费时间明显增加;在前肢悬挂实验中悬挂时间显著下降。3.神经行为学。三箱社交实验,T迷宫自发性选择实验、旷场实验、埋珠实验、开场实验中,联合模型组表现为更加明显的社交缺陷、重复刻板行为和焦虑行为。机制探讨。1.模型组孤独症大鼠可见:前额皮质组织形态结构受损;lsd1酶活性升高;UCP2蛋白和Ucp2 mRNA水平下降;SOD活性、GSH和ATP水平显著下降;KCC2下调和NKCC1上调,MQAE荧光强度显著降低指示细胞内氯离子浓度增高;GABA水平降低,Glu和Glu/GABA比值水平升高;GABRG2蛋白表达下降,并且GABRG2与Gephyrin共定位系数显著降低。2.lsd1抑制剂TAK-418干预后可减轻ASD样行为,表现为:孤独症大鼠模型前额皮质病理组织损伤缓解;lsd1酶活性降低;UCP2蛋白和Ucp2 mRNA表达升高;SOD活性、GSH和ATP水平增高;KCC2上调和NKCC1下调进而降低细胞内氯离子浓度;GABA水平升高,Glu水平和Glu/GABA比值降低;GABRG2蛋白表达及GABRG2与Gephyrin共定位系数升高。结论:我们成功构建新型孤独症大鼠模型,发现lsd1通过下调UCP2诱导氧化损伤引起氯离子转运蛋白失调,导致氯稳态破坏和GABA系统兴奋抑制失衡与孤独症有关,而TAK-418干预可改善ASD大鼠孤独症样行为。

关键词：孤独症铝 lsd1 E/I 氯稳态

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HMG20A调控猪肌内脂肪生成的功能和机制研究

HMG20A调控猪肌内脂肪生成的功能和机制研究

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作者：孟珊山西农业大学

学位级别：硕士

肌内脂肪(Intramuscular Fat,IMF)在猪肉品质性状中起着关键作用,肌内脂肪含量的累积主要取决于肌内脂肪细胞的数量和大小,而脂肪细胞的生成是一个受到以转录因子为核心的转录级联网络调控的过程。转录因子HMG20A(HMG domain protein 20... 详细信息

肌内脂肪(Intramuscular Fat,IMF)在猪肉品质性状中起着关键作用,肌内脂肪含量的累积主要取决于肌内脂肪细胞的数量和大小,而脂肪细胞的生成是一个受到以转录因子为核心的转录级联网络调控的过程。转录因子HMG20A(HMG domain protein 20A,HMG20A)是高迁移率家族的成员,研究已证实HMG20A在神经元分化、上皮间质转化以及Ⅱ型糖尿病发生过程中发挥着重要的调控作用,而本试验利用前期研究数据发现,HMG20A在猪肌内前体脂肪细胞成脂分化早期表达量显著升高,可能是调控脂肪生成的关键因子,但其调控机制尚不明确。因此,本研究通过PCR扩增获得猪HMG20A基因的CDS区,并对其进行生物学特性分析;随后通过基因功能“缺失”和“获得”研究HMG20A对成脂分化的影响;利用转录组测序寻找HMG20A的下游靶基因进而揭示下游调控机制。后通过lncRNA测序结合干扰HMG20A试验结果,筛选HMG20A的下游lncRNA,并对其调控成脂分化的功能进行研究。研究结果如下:1、HMG20A在马身猪肌肉组织中的表达量显著高于大白猪(P1044 bp,编码347个氨基酸,该基因及其所编码的蛋白在不同物种中高度保守。在猪肌内前体脂肪细胞中干扰HMG20A并诱导分化7 d后,油红O染色发现成熟的脂滴明显增多,q RTPCR结果显示CEBPα、PPARγ和FABP4的mRNA表达量均显著升高(P10T1/2细胞中干扰HMG20A并进行诱导分化后,结果显示脂滴显著增多,成脂关键基因CEBPα、LPL和FABP4的mRNA表达量显著升高(P1),表明干扰HMG20A促进C3H10T1/2细胞的成脂分化;过表达HMG20A后则抑制C3H10T1/2细胞的成脂分化,说明HMG20A物种功能的保守性较高。2、为了揭示HMG20A的下游调控机制,通过转录组测序和比较分析,干扰HMG20A组与对照组相比,有271个显著差异基因,其中上调基因171个,下调基因100个。GO和KEGG结果显示,差异基因主要富集在MAPK信号通路和JAK-STAT信号通路等。通过体外干扰、过表达试验以及h TFtarget数据库预测证明了差异表达基因MEF2C为HMG20A的潜在靶基因。利用Co IP技术发现HMG20A和lsd1存在蛋白互作关系,CHIP-q PCR结果显示干扰HMG20A后降低了MEF2C启动子区域的H3K4me2修饰(P1)和mRNA表达(Plsd1后,缓解了HMG20A对MEF2C的促进作用并抑制了成脂分化。3、为研究HMG20A与表观遗传调控分子lncRNA之间是否存在调控关系,试验通过比较分析1日龄马身猪与大白猪背最长肌中差异表达的lncRNA,随后在干扰HMG20A后发现差异表达的lncRNA-6617的表达量极显著下调(P1)。生物信息学分析发现lncRNA-6617位于猪18号染色体上,无蛋白编码能力。核质分离结果显示,lncRNA-6617主要分布于细胞核。q RT-PCR结果显示其在各个组织中均有表达,且在猪肌内前体脂肪细胞的分化过程中表达量呈上升趋势。在猪肌内前体脂肪细胞中干扰lncRNA-6617并进行诱导分化后,油红O染色发现分化的成熟脂肪细胞显著减少,q RTPCR结果显示CEBPα、PPARγ和FABP4的表达均极显著下调(P1),表明干扰lncRNA-6617抑制猪肌内前体脂肪细胞成脂分化。综上所述,本研究发现HMG20A是调控脂肪细胞生成的负调控因子。HMG20A通过与lsd1互作调控下游靶基因MEF2C的组蛋白修饰,进而调控脂肪细胞生成。同时,本研究发现HMG20A还可通过改变lncRNA-6617的表达调控猪肌内脂肪细胞成脂分化。本研究初步探究了HMG20A调控肌内脂肪生成的作用及机制,丰富了肌内脂肪生成调控网络。

关键词：猪肌内脂肪 HMG20A 成脂分化 lsd1

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