Regulation of the brown and white fat gene programs through a PRDM16/CtBP transcriptional complex
Regulation of the brown and white fat gene programs through a PRDM16/CtBP transcriptional complex
复制标题
DOI：
10.1101/gad.1666108
复制
发表时间：
2008-05-15
影响因子：
10.5
通讯作者：
Spiegelman, Bruce M.
中科院分区：
文献类型：
--
作者：
Kajimura, Shingo;Seale, Patrick;Spiegelman, Bruce M.
棕色脂肪是一种特殊的组织，可以通过一种基因表达模式来消耗能量和对抗肥胖，这种基因表达模式大大增加了线粒体含量和非偶联呼吸。PRDM 16是一种锌指蛋白，通过刺激棕色脂肪选择性基因表达，同时抑制选择性用于白色脂肪细胞的基因表达，来控制棕色脂肪测定。为了确定调节这种基因程序转换的机制，我们从脂肪细胞中纯化了天然PRDM 16蛋白复合物。我们发现PRDM 16转录holocompex包含C-末端结合蛋白-1（CtBP-1）和CtBP-2，这种直接相互作用选择性地介导白色脂肪基因的抑制。这种抑制是通过将PRDM 16/CtBP复合物募集到白色脂肪特异性基因（例如抵抗素）的启动子上而发生的，并且在CtBP-1和CtBP-2基因缺失的情况下被消除。反过来，PPAR-gamma-coactivator-1 alpha（PGC-1 alpha）和PGC-1 beta募集到PRDM 16复合物中取代了CtBP，使该复合物能够有力地激活棕色脂肪基因，如PGC-1 alpha本身。这些数据表明，CtBP蛋白在PRDM 16上的调节对接控制棕色和白色脂肪选择性基因程序。
Brown fat is a specialized tissue that can dissipate energy and counteract obesity through a pattern of gene expression that greatly increases mitochondrial content and uncoupled respiration. PRDM16 is a zinc-finger protein that controls brown fat determination by stimulating brown fat-selective gene expression, while suppressing the expression of genes selective for white fat cells. To determine the mechanisms regulating this switching of gene programs, we purified native PRDM16 protein complexes from fat cells. We show here that the PRDM16 transcriptional holocompex contains C-terminal-binding protein-1 CtBP-1) and CtBP-2, and this direct interaction selectively mediates the repression of white fat genes. This repression occurs through recruiting a PRDM16/CtBP complex onto the promoters of white fat-specific genes such as resistin, and is abolished in the genetic absence of CtBP-1 and CtBP-2. In turn, recruitment of PPAR-gamma-coactivator-1 alpha PGC-1 alpha) and PGC-1 beta to the PRDM16 complex displaces CtBP, allowing this complex to powerfully activate brown fat genes, such as PGC-1 alpha itself. These data show that the regulated docking of the CtBP proteins on PRDM16 controls the brown and white fat-selective gene programs.