棕色脂肪细胞特异基因PRDM16的研究进展与展望

Advances and Prospects of Brown Adipocyte-Specific Gene PRDM16

PR结构域蛋白16(PR domain-containing 16,PRDM16)是棕色脂肪细胞分化过程的重要转录因子,其对维持棕色脂肪细胞的特殊形态特征及细胞功能具有重要的作用。PRDM16不仅能调控棕色脂肪细胞的分化,而且可能是脂肪细胞和肌细胞相互转化的"开关",还与白色脂肪细胞的米色化过程相关。研究发现,人和家畜的PRDM16基因具有丰富的SNPs位点,这些SNPs位点与人类疾病和家畜生产性状之间存在着一定的相关性。鉴于PRDM16在脂肪分化和人类健康等方面的重要性,综述了近十几年来国内外研究者在PRDM16基因与PRDM16蛋白的结构与功能、该基因与疾病和家畜经济性状的相关性等方面的研究成果,并展望了PRDM16的未来研究方向与在人类疾病治疗和动物性状改良方面的应用前景。

PRDM16 (PR domain-containing 16) is a 16 th member of PR domain family,was firstly found in a patient with leukemia and was initially thought to be related to myelodysplastic syndrome (MDS) and chronic myelogenous leukemia (CML). PRDM16 contains six important functional domains,including PR domain (PR),zinc finger domain 1 (ZF-1),proximal regulatory region (PRR),repression domain (RD),zinc finger domain 2 (ZF-2),and acidic activation domain (AD),respectively. The ablation of PR domain which is an exclusive domain for PRDM family has been linked to MDS and CML;the domains of ZF-1 and ZF-2 are capable to bind to peroxisome proliferator-activated receptor-α/γ(PPAR-α/γ),CCAAT-enhancer binding proteins-β(CEBP-β),peroxisome proliferator-activated receptor-γ coactivator1-α/β(PGC1-α/β) and mediator complex subunit 1 (MED1);the RD domain is main site for PRDM16 to bind with C-terminal binding protein-1/2 (CtBP-1/2). In mammals,the PRDM16 is involved in a spectrum of biological processes including cell fate determination and development. The PRDM16 is capable to regulate transcription via intrinsic chromatin-modifying,complexing with histone-modifying. Studies have shown the pivotal roles of PRDM16 in the determination and functions of brown and beige fat cell,as well as in thermogenesis,hematopoiesis and cardiac development. Studies indicated that PRDM16 is a key transcriptional regulator in differentiation of the brown adipocytes. PRDM16 has been found has an important role in maintaining "brown fat cell-specific " morphological properties and biological functions,as well as in association with high abundant mitochondria contents and its thermogenesis capacity.PRDM16 controls a "bidirectional cell fate switch"for skeletal myoblasts and brown fat cells. It involves in a"browning"process in white adipose tissues,which transform white adipocytes into brown/beige adipocytes.PRDM16 has also been related to the increase of visceral fat which may cause the immune response in animals.In the process of "browning",many transcriptional factors were recruited to the promoter or enhancer regions of brown fat-related genes by regulation of PRDM16 through its ZF-1/2 domain. This,in turn,eventually promotes genes expression and BAT differentiation. And the recruit of C-terminal banding protein in the promoter of white fat cell-related genes makes them repressed by PRDM16 via its PLDLS motif in the repression domain. Recently,the genetic variations in the PRDM16 gene were identified,in humans and livestock and have been associated with a spectrum of diseases and production traits. Those reported SNPs in PRDM16 were summarized. The SNPs in human PRDM16 were significantly associated with risk of diseases such as dilated cardiomyopathy,dyslipidemia,migraine without aura and metabolic syndrome. In livestock,variations of PRDM16 have been mainly associated with growth traits and other important economic traits,including body weight,body size and carcass weight. Because of the potential applications of PRDM16 in treating human diseases and improving economic traits in livestock,the future research areas may focus on understanding the mechanism underlying the action of PRDM16 in adipose biology which may have relevance to other PRDM family members. This new knowledge may also have the potential to be exploited for therapeutic and breeding benefits.