Friends-Enemies: Endogenous Retroviruses Are Major Transcriptional Regulators of Human DNA.
Friends-Enemies: Endogenous Retroviruses Are Major Transcriptional Regulators of Human DNA.
复制标题
DOI：
10.3389/fchem.2017.00035
复制
发表时间：
2017
影响因子：
5.5
通讯作者：
Garazha AV
中科院分区：
文献类型：
--
作者：
Buzdin AA;Prassolov V;Garazha AV
内源性逆转录病毒是在插入宿主DNA时与感染性或“外源性”逆转录病毒难以区分的移动遗传元件。人内源性逆转录病毒（herv）并不罕见。它们产生了多个密切相关的可移动元件家族，占人类基因组的8%左右。它们共同通过提供位于约11万个HERV元件上的至少32万个人类转录因子结合位点（TFBS）来塑造基因组调控格局。herv宿主多达155,000个定位的dna ei超敏位点，这些位点表示在基因表达或染色质结构调节中活跃的位点。当前对HERV进化动力学的观点表明，在插入后的早期阶段，HERV被宿主细胞视为外来遗传元件，并可能被靶向甲基化和突变抑制。然而，在后期阶段，当大量的突变已经积累，当逆转录病毒基因被破坏时，HERV的调控潜力可能被释放并被招募来修改转录因子结合位点的基因组平衡。这一过程伴随着突变的进一步积累和选择，从而重塑了人类DNA的调控格局。然而，发育重编程，压力或病理条件，如癌症，炎症和传染病，可以消除限制表达和herv介导的宿主基因调控的块。这反过来又会极大地改变基因表达平衡，并将其转移到一个新的状态，从而进一步放大不稳定性，加剧压力状况。
Endogenous retroviruses are mobile genetic elements hardly distinguishable from infectious, or “exogenous,” retroviruses at the time of insertion in the host DNA. Human endogenous retroviruses (HERVs) are not rare. They gave rise to multiple families of closely related mobile elements that occupy ~8% of the human genome. Together, they shape genomic regulatory landscape by providing at least ~320,000 human transcription factor binding sites (TFBS) located on ~110,000 individual HERV elements. The HERVs host as many as 155,000 mapped DNaseI hypersensitivity sites, which denote loci active in the regulation of gene expression or chromatin structure. The contemporary view of the HERVs evolutionary dynamics suggests that at the early stages after insertion, the HERV is treated by the host cells as a foreign genetic element, and is likely to be suppressed by the targeted methylation and mutations. However, at the later stages, when significant number of mutations has been already accumulated and when the retroviral genes are broken, the regulatory potential of a HERV may be released and recruited to modify the genomic balance of transcription factor binding sites. This process goes together with further accumulation and selection of mutations, which reshape the regulatory landscape of the human DNA. However, developmental reprogramming, stress or pathological conditions like cancer, inflammation and infectious diseases, can remove the blocks limiting expression and HERV-mediated host gene regulation. This, in turn, can dramatically alter the gene expression equilibrium and shift it to a newer state, thus further amplifying instability and exacerbating the stressful situation.