Davidson Brigid S A, Arcila-Galvis Juliana Estefania, Trevisan-Herraz Marco, Mikulasova Aneta, Brackley Chris A, Russell Lisa J, Rico Daniel
Biosciences Institute, Newcastle University, Newcastle upon Tyne, United Kingdom.
SUPA, School of Physics and Astronomy, University of Edinburgh, Edinburgh, United Kingdom.
Front Cell Dev Biol. 2024 Jul 30;12:1294510. doi: 10.3389/fcell.2024.1294510. eCollection 2024.
The gene () 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 overexpression affects cancerous tissues. In this work, we show that has likely originated and may still function as an enhancer, regulating and . Firstly, 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 in multiple healthy human tissues, which include B cells, liver and lung tissue. The analysis of 3D genome datasets revealed chromatin interactions between a ' and the proto-oncogene . 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 orthologues. Furthermore, we observed conservation of an active enhancer state in the orthologues of four non-human primates, dogs, rats, and mice. When studying this homologous region in mice, where the ORF of is absent, we not only observed an enhancer chromatin state but also found interactions between the mouse enhancer homolog and 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 is a primate-specific gene with a ORF that originated at an evolutionarily older enhancer region. This deeply conserved putative enhancer element could regulate in both humans and mice, opening the possibility of studying regulatory functions in cancer using non-primate animal models.
由于在多种癌症（包括骨髓瘤、乳腺癌、肺癌、胰腺癌和食管癌）中发现该基因（）的RNA转录水平很高，因此它被认为是一种原癌基因。在人类和其他灵长类动物中存在开放阅读框（ORF）表明其具有蛋白质编码潜力。然而，我们仍然缺乏功能性MYEOV蛋白的证据。目前尚不清楚该基因的过表达如何影响癌组织。在这项研究中，我们表明该基因可能起源于并可能仍然作为一种增强子发挥作用，调控和。首先，利用公开的ATAC-STARR-seq数据在人类B细胞来源的GM12878细胞上证实了该基因3'端的增强子活性。我们在包括B细胞、肝脏和肺组织在内的多种健康人体组织中检测到增强子组蛋白标记H3K4me1和H3K27ac与该基因重叠。对三维基因组数据集的分析揭示了该基因的一个“和原癌基因之间的染色质相互作用。BLAST搜索和多序列比对结果表明，来自该人类增强子元件的DNA序列自两栖动物/羊膜动物分化以来一直保守，在所有哺乳动物中甚至在鸡中也发现了一个273 bp的保守区域，并且它始终位于相应的直系同源基因附近。此外，我们在四种非人类灵长类动物、狗、大鼠和小鼠的直系同源基因中观察到了活跃增强子状态的保守性。在小鼠中研究这个同源区域时，由于小鼠中不存在该基因的ORF，我们不仅观察到了增强子染色质状态，还利用三维基因组相互作用数据发现了小鼠增强子同源物与该基因之间的相互作用。这与在人类中观察到的相互作用相似，有趣的是，在两个物种中都与CTCF结合位点一致。综上所述，这表明该基因是一个具有ORF的灵长类特异性基因，它起源于一个进化上更古老的增强子区域。这个深度保守的假定增强子元件可能在人类和小鼠中调控该基因，这为使用非灵长类动物模型研究该基因在癌症中的调控功能开辟了可能性。
