背景:普遍使用替代启动子会导致癌变过程中基因表达的失调,并可能推动精子发生中新基因的出现。然而,关于支持替代启动子激活的机制知之甚少。
结果:这里我们描述了癌症-睾丸特异性转录是如何被激活的。我们显示了基因间和内含子CTCF结合位点,在正常体细胞中转录惰性,可以在胚芽和癌细胞中表观遗传学重编程为活跃的从头启动子。BORIS/CTCFL,广泛表达的CTCF的睾丸特异性旁系,触发CTCF位点的表观遗传重编程为活性转录单元。BORIS结合启动了染色质重塑因子的募集,SRCAP,然后用H2A替换H2A组蛋白。Z,导致CTCF结合位点侧翼的核小体中更松弛的染色质状态。CTCF结合位点周围染色质的松弛促进了多种其他转录因子的募集。从而激活从给定结合位点的转录。我们证明了表观遗传重编程的CTCF结合位点可以驱动癌症睾丸基因的表达,长链非编码RNA,逆转录伪基因,和休眠的转座因子。
结论:因此,BORIS作为一种转录因子,表观遗传重编程聚集的CTCF结合位点进入转录起始位点,促进生殖细胞和癌细胞中替代启动子的转录。
Pervasive usage of alternative promoters leads to the deregulation of gene expression in carcinogenesis and may drive the emergence of new genes in spermatogenesis. However, little is known regarding the mechanisms underpinning the activation of alternative promoters.
Here we describe how alternative cancer-testis-specific transcription is activated. We show that intergenic and intronic
CTCF binding sites, which are transcriptionally inert in normal somatic cells, could be epigenetically reprogrammed into active de novo promoters in germ and cancer cells. BORIS/CTCFL, the testis-specific paralog of the ubiquitously expressed
CTCF, triggers the epigenetic reprogramming of
CTCF sites into units of active transcription. BORIS binding initiates the recruitment of the chromatin remodeling factor, SRCAP, followed by the replacement of H2A histone with H2A.Z, resulting in a more relaxed chromatin state in the nucleosomes flanking the
CTCF binding sites. The relaxation of chromatin around
CTCF binding sites facilitates the recruitment of multiple additional transcription factors, thereby activating transcription from a given binding site. We demonstrate that the epigenetically reprogrammed CTCF binding sites can drive the expression of cancer-testis genes, long noncoding RNAs, retro-pseudogenes, and dormant transposable elements.
Thus, BORIS functions as a transcription factor that epigenetically reprograms clustered CTCF binding sites into transcriptional start sites, promoting transcription from alternative promoters in both germ cells and cancer cells.