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Lookup NU author(s): Brigid Davidson, Dr Juliana Arcila Galvis, Dr Marco Trevisan-HerrazORCiD, Dr Aneta Mikulasova, Dr Lisa Russell, Dr Daniel Rico Rodriguez
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
Copyright © 2024 Davidson, Arcila-Galvis, Trevisan-Herraz, Mikulasova, Brackley, Russell and Rico.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.
Author(s): Davidson BSA, Arcila-Galvis JE, Trevisan-Herraz M, Mikulasova A, Brackley CA, Russell LJ, Rico D
Publication type: Article
Publication status: Published
Journal: Frontiers in Cell and Developmental Biology
Year: 2024
Volume: 12
Online publication date: 30/07/2024
Acceptance date: 01/07/2024
Date deposited: 27/08/2024
ISSN (electronic): 2296-634X
Publisher: Frontiers Media SA
URL: https://doi.org/10.3389/fcell.2024.1294510
DOI: 10.3389/fcell.2024.1294510
Data Access Statement: Publicly available datasets were analyzed in this study. The sources of the datasets can be found in Supplementary Table S1. https://www.frontiersin.org/journals/cell-and-developmental-biology/articles/10.3389/fcell.2024.1294510/full#SM1
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