由于在多种癌症中发现的高RNA转录水平,骨髓瘤过表达基因(MYEOV)已被认为是原癌基因。包括骨髓瘤,乳房,肺,胰腺癌和食道癌。人类和其他灵长类动物中开放阅读框(ORF)的存在表明蛋白质编码潜力。然而,我们仍然缺乏功能性MYEOV蛋白的证据。尚未确定MYEOV过表达如何影响癌组织。在这项工作中,我们表明MYEOV可能已经起源,并且仍然可以作为增强剂,调节CCND1和LTO1。首先,使用公开的ATAC-STARR-seq数据证实了人类的MYEOV3增强子活性,在B细胞来源的GM12878细胞上进行。我们在多个健康人体组织中检测到增强子组蛋白标记H3K4me1和H3K27ac重叠MYEOV,其中包括B细胞,肝和肺组织。对3D基因组数据集的分析揭示了MYEOV-3推定增强子与原癌基因CCND1之间的染色质相互作用。BLAST搜索和多序列比对结果表明,这种人类增强子元件的DNA序列与两栖动物/羊膜生物的分歧是保守的,在所有哺乳动物中也发现了273bp的保守区域,甚至在鸡身上,它始终位于相应的CCND1直系同源物附近。此外,我们观察到四个非人灵长类动物的MYEOV直向同源物中的活性增强子状态的保守性,狗,老鼠,和老鼠。当研究小鼠的这个同源区域时,没有MYEOV的ORF,我们不仅观察到了增强子染色质状态,而且使用3D基因组相互作用数据发现了小鼠增强子同源物和Ccnd1之间的相互作用.这类似于在人类中观察到的相互作用,有趣的是,与两个物种的CTCF结合位点一致。一起来看,这表明MYEOV是一种灵长类动物特异性基因,具有起源于进化上较老的增强子区域的从头ORF。这种高度保守的推定增强子元件可以调节人和小鼠的CCND1,开启了使用非灵长类动物模型研究癌症中MYEOV调节功能的可能性。
The myeloma overexpressed gene (MYEOV) has been proposed to be a proto-oncogene due to high RNA transcript levels found in multiple cancers, including myeloma, breast, lung, pancreas and esophageal cancer. The presence of an open reading frame (ORF) in humans and other primates suggests protein-coding potential. Yet, we still lack evidence of a functional MYEOV protein. It remains undetermined how MYEOV overexpression affects cancerous tissues. In this work, we show that MYEOV has likely originated and may still function as an
enhancer, regulating CCND1 and LTO1. Firstly, MYEOV 3\'
enhancer activity was confirmed in humans using publicly available ATAC-STARR-seq data, performed on B-cell-derived GM12878 cells. We detected enhancer histone marks H3K4me1 and H3K27ac overlapping MYEOV in multiple healthy human tissues, which include B cells, liver and lung tissue. The analysis of 3D genome datasets revealed chromatin interactions between a MYEOV-3\'-putative
enhancer and the proto-oncogene CCND1. BLAST searches and multi-sequence alignment results showed that DNA sequence from this human
enhancer element is conserved from the amphibians/amniotes divergence, with a 273 bp conserved region also found in all mammals, and even in chickens, where it is consistently located near the corresponding CCND1 orthologues. Furthermore, we observed conservation of an active enhancer state in the MYEOV orthologues of four non-human primates, dogs, rats, and mice. When studying this homologous region in mice, where the ORF of MYEOV is absent, we not only observed an enhancer chromatin state but also found interactions between the mouse enhancer homolog and Ccnd1 using 3D-genome interaction data. This is similar to the interaction observed in humans and, interestingly, coincides with CTCF binding sites in both species. Taken together, this suggests that MYEOV is a primate-specific gene with a de novo ORF that originated at an evolutionarily older enhancer region. This deeply conserved putative
enhancer element could regulate CCND1 in both humans and mice, opening the possibility of studying MYEOV regulatory functions in cancer using non-primate animal models.