The Proceedings of the Eighth International Conference on Creationism (2018)

(ATGCAAAG). Only LTR5HS of the HML-2 subgroup of HERVK contain both elements. There are two other types of LTRs within HML-2, LTR5a and LTR5b, which do not respond to progesterone because they lack the octomer and have poorly conserved PREs. It seems that only a narrow category of HERMK (HML-2) respond to sex hormones. LTR5HS was originally thought to be human- specific, but a close examination found some LTR5HS elements are shared between human and chimpanzee, and there is at least one chimpanzee-specific solo LTR5HS (Buzdin et al. 2003). All LTR5HS elements should respond to progesterone because their sequences are highly conserved and all contain identical PRE and the octamer. However, they may not affect transcription of downstream sequences, depending on the presence or absence of transcription termination signals. Our findings offer direct support to the notion that the HERVs were created in the human genome to simultaneously regulate genes that are scattered throughout the genome. In addition, these elements are interwoven into a complex network of regulatory factors in the human body including sex hormones, hormone receptors, and other transcription factors such as OCT4. DNA methylation has been considered a major mechanism by which the cell silences the HERV sequences. While this is still largely true, we just found that methylation of certain cytosine residues within HERVs actually facilitates their upregulation by progesterone. Instead of simply silencing HERVs, some cells seem to have delicate mechanisms to modulate their expression up or down according to their need. HERVKs are the most intact class of ERVs in the human genome. Based on positional polymorphism within human genomes, transposition of HERVKs may have occurred in the recent past (Belshaw et al. 2005; Hughes and Coffin 2004). We are unclear about the effects of the individual HERVK genes on the cell, but full-length HERVKs may have been designed as units with abilities of regulated expression, moving around in the genome (transposition), packaging into viral particles, and even transmission between cells and hosts. However, most HERVs are so degenerate that some of these abilities may have been lost. The significance of hormone-regulated, LTR-driven transcription of host DNA still awaits further studies. The role of HERVs in carcinogenesis has been a subject of much speculation (Nelson et al. 2003). Our preliminary findings indicate that activation of HERVs comes after OCT4 expression and DNA hypomethylation, therefore it is more likely a result, rather than the cause, of carcinogenesis. The role of OCT4 in carcinogenesis is still debated, even though it is active in tumor-initiating cells (Wang and Herlyn 2015). Clarification of the potential interactions and collaborations between hormones and OCT4 in breast cancer cells may shed light on fundamental questions in cancer biology. The indication that progesterone acts partially through OCT4 sheds light on a long-standing puzzle: ERVs are not expressed in normal breast tissues with or without hormonal treatment, but are expressed in some breast cancer cells, especially in response to progesterone (Wang-Johanning et al. 2001). It also explains the association between ERV activity and breast cancer prognosis (Liu et al. 2014; Zhao et al. 2011). In addition, the link between progesterone and OCT4 provides a theoretical basis for the therapeutic effect of progesterone antagonists/modulators in some breast cancer cases. Further research in this field may improve our understanding of breast cancer pathogenesis, guide treatment of breast cancer with hormones, and even lead to new anticancer approaches based on suppression of OCT4. If the progesterone receptor prefers methylated DNA, or mediates different effects when bound to methylated and unmethylated DNA, it will affect expression of ERVs in germline cells and during early embryonic development, when DNA is demethylated and remethylated. The finding will also have profound implications in hormone physiology and hormone therapies, as demethylating agents may affect the potency of progesterone receptor modulators. Additionally, oncologists will have to watch for consequences of endocrine dysregulation and HERV activation when demethylating agents are used in chemotherapy. CONCLUSION: Coordinated regulation of human endogenous retroviruses and solo LTR elements suggest that they were designed to mediate the action of hormones and/or other physiological signals to regulate expression of interspersed genes. Interactions of ERV elements and DNA methylation enzymes, hormone receptors, and other transcription factors such as OCT4 indicate that HERVs are integral parts of the human genome. At least some of them must have been created at the beginning of mankind. Structural and positional homology of HERVs between humans and animals are more likely due to functional necessity rather than common descent. REFERENCES Ball, M., M. Carmody, F. Wynne, P. Dockery, A. Aigner, I. Cameron, J. Higgins, S.D. Smith, J.D. Aplin, and T. Moore. 2009. Expression of pleiotrophin and its receptors in human placenta suggests roles in trophoblast life cycle and angiogenesis. Placenta 30, no. 7:649-653. Belshaw, R., A. L. A. Dawson, J. Woolven-Allen, J. Redding, A. Burt, and M. Tristem. 2005. Genomewide screening reveals high levels of insertional polymorphism in the human endogenous retrovirus family HERV-K(HML2): implications for present-day activity. Journal of Virology 79, no. 19: 12507-12514. Bergman J. 1999. Did God make pathogenic viruses? Journal of Creation 13, no. 1:115-125. Buzdin, A., S. Ustyugova, K. Khodosevich, I. Mamedov, Y. Lebedev, G. Hunsmann, and E. Sverdlov. 2003. Human-specific subfamilies of HERV-K (HML-2) long terminal repeats: three master genes were active simultaneously during branching of hominoid lineages. Genomics 81, no. 2:149-156. Fabich, A. 2015. Do endogenous retroviruses (ERVs) support common ancestry? Retrieved February 16, 2018 from https://answersingenesis. org/biology/microbiology/endogenous-retroviruses-common-ancestry/ Gogvadze, E., E. Stukacheva, A. Buzdin, and E. Sverdlov. 2009. Human- specific modulation of transcriptional activity provided by endogenous retroviral insertions. Journal of Virology 83, no. 12:6098-6105. Golan, M., A. Hizi, J. H. Resau, N. Yaal-Hahoshen, H. Reichman, I. Keydar, and I. Tsarfaty. 2008. Human Endogenous Retrovirus (HERV-K) Reverse Transcriptase as a Breast Cancer Prognostic Marker. Neoplasia 10:521-533. Grow, E. J., R. A. Flynn, S. L. Chavez, N. L. Bayless, M. Wossidlo, D. J. Wesche, L. Martin, C. B. Ware, C. A. Blish, H. Y. Chang, R. A. Reijo Pera, and J. Wysocka. 2015. Intrinsic retroviral reactivation in human Liu and Nguyen ◀ Endogenous Retroviruses ▶ 2018 ICC 198