Cross Talk Between GH-Regulated Transcription Factors HNF6 and CUX2 in Adult Mouse Liver
Cross Talk Between GH-Regulated Transcription Factors HNF6 and CUX2 in Adult Mouse Liver
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DOI：
10.1210/me.2015-1028
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发表时间：
2015-09-01
影响因子：
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通讯作者：
Waxman, David J.
中科院分区：
文献类型：
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作者：
Conforto, Tara L.;Steinhardt, George F.;Waxman, David J.
肝细胞富集核因子（HNF）6和CUX2是GH和stat5调控的同源盒转录因子。CUX2表现出女性特异性表达，通过抑制许多男性偏倚基因和诱导许多女性偏倚基因而导致肝脏性别差异，而HNF6在男性和女性肝脏中的表达水平相似。在细胞转染研究中，CUX2抑制HNF6对性别特异性基因启动子CYP2C11和CYP2C12的转录调控，阻断HNF6对CYP2C11的抑制和HNF6对CYP2C12的激活。CUX2的这些抑制作用可以通过竞争HNF6 DNA结合来解释，这一点在体外EMSA分析中得到了证实，并在体内通过对HNF6细胞的全局分析得到了验证。在小鼠肝染色质中鉴定出约40000个HNF6结合位点，其中数千个位点在HNF6结合上显示出显著的性别差异。这些性别偏倚的hnf6结合位点显示出相应的性别偏倚的dna酶敏感位点的强烈富集，以及与显示局部性别偏倚的染色质标记和相应的性别偏倚表达的基因的接近。此外，大约90%的CUX2全基因组结合位点也被HNF6结合。这些HNF6/CUX2的共同结合位点在雄性小鼠的肝染色质中比雌性小鼠更易接近的基因组区域中富集，并且在雄性偏倚基因中表现出最强的富集，这表明CUX2取代HNF6可能是雌性小鼠肝脏中CUX2抑制雄性偏倚基因的一种机制。HNF6在其大多数结合位点是性别独立的，并且HNF6的峰值经常与多个其他肝脏转录因子的共结合相关，这与HNF6在男性和女性肝脏中发挥全局调节作用一致。
Hepatocyte-enriched nuclear factor (HNF)6 and CUX2 are GH and STAT5-regulated homeobox transcription factors. CUX2 shows female-specific expression and contributes to liver sex differences by repressing many male-biased genes and inducing many female-biased genes, whereas HNF6 is expressed at similar levels in male and female liver. In cell-based transfection studies, CUX2 inhibited HNF6 transcriptional regulation of the sex-specific gene promoters CYP2C11 and CYP2C12, blocking HNF6 repression of CYP2C11 and HNF6 activation of CYP2C12. These inhibitory actions of CUX2 can be explained by competition for HNF6 DNA binding, as demonstrated by in vitro EMSA analysis and validated in vivo by global analysis of the HNF6 cistrome. Approximately 40 000 HNF6-binding sites were identified in mouse liver chromatin, including several thousand sites showing significant sex differences in HNF6 binding. These sex-biased HNF6-binding sites showed strong enrichment for correspondingly sex-biased DNase hypersensitive sites and for proximity to genes showing local sex-biased chromatin marks and a corresponding sex-biased expression. Further, approximately 90% of the genome-wide binding sites for CUX2 were also bound by HNF6. These HNF6/CUX2 common binding sites were enriched for genomic regions more accessible in male than in female mouse liver chromatin and showed strongest enrichment for male-biased genes, suggesting CUX2 displacement of HNF6 as a mechanism to explain the observed CUX2 repression of male-biased genes in female liver. HNF6 binding was sex independent at a majority of its binding sites, and HNF6 peaks were frequently associated with cobinding by multiple other liver transcription factors, consistent with HNF6 playing a global regulatory role in both male and female liver.