摘要
Polycomb group complex(Pc G)作为发挥转录抑制作用的重要表观遗传调控复合物,参与发育、衰老以及肿瘤发生等重要病生理过程。Pc G成员众多,分为PRC1与PRC2两种复合物,各组分间功能既协同,又不失特性。PRC1中的CBX4独特的结构域使其功能尤为特殊。近年发现,作为一类造血干细胞恶性克隆性疾病,白血病中常伴有Pc G基因的异常表达或者突变。本研究通过q PCR发现,在慢性粒细胞白血病(chronic myeloid leukemia,CML)患者外周血白细胞中存在CBX4的表达明显下调,而Pc G经典靶基因HOX家族中的HOXA5则表现为上调。给予伊马替尼(Imatinib)治疗后,二者均向相反方向恢复至正常人的表达水平,并且CBX4的表达水平与CML的经典分子标志物BCR-ABL1融合基因有较好的相关性。上述结果提示,CBX4可以作为CML潜在的预后标志物。为了进一步揭示CBX4与HOXA5是否存在相互作用关系,本文通过双荧光素酶实验证实,CBX4能通过HOXA5的启动子而负调控其表达。本研究发现,CBX4与HOXA5在CML中存在负相关的异常表达,且证明CBX4可作为HOXA5的负调控因子。
Polycomb group（ Pc G）,as the key transcriptional repressor,plays an important role in epigenetic regulation for target genes expression and is involved in a diverse range of processes such as development,senescence and tumorigenesis etc. Pc G consists of two multiprotein complexes,polycomb repressive complex 1（ PRC1） and PRC2,in which each component coordinates but presents distinct function. CBX4 is a representative component within PRC1. Recently,aberrant expression and mutation of Pc G genes were detected in hematopoietic neoplasms. In this study,we found that CBX4 was downregulated in chronic myeloid leukemia（ CML） peripheral blood. Upon Imatinib treatment,CBX4 was restored to normal level. The canonical target of Pc G,HOXA5,was found upregulated in an opposite pattern in CML and was restored to normal level upon Imatinib treatment. A good correlation between CBX4 expression level and CML classic molecular marker BCR-ABL1 fusion gene was also found. The result suggested that CBX4 could be a potential CML prognostic marker. In order to know whether CBX4 interacted with HOXA5,CBX4 was knocked down or knocked in within 293 T cells. Through dual luciferase assay,we confirmed that CBX4 could act on the HOXA5 promoter to negatively control its expression. This study proved that CBX4 could act as a negative regulator of HOXA5,which provided evidence for both CBX4 and HOXA5 as potential biomarkers of CML and other types of leukemia.
出处
《中国生物化学与分子生物学报》
CAS
CSCD
北大核心
2016年第9期1048-1053,共6页
Chinese Journal of Biochemistry and Molecular Biology
基金
国家自然科学基金项目(No.31071206
No.81541142
No.81672091)资助~~
