Retroelement-Linked H3K4me1 Histone Tags Uncover Regulatory Evolution Trends of Gene Enhancers and Feature Quickly Evolving Molecular Processes in Human Physiology

Abstract

Background: Retroelements (REs) are mobile genetic elements comprising ~40% of human DNA. They can reshape expression patterns of nearby genes by providing various regulatory sequences. The proportion of regulatory sequences held by REs can serve a measure of regulatory evolution rate of the respective genes and molecular pathways. Methods: We calculated RE-linked enrichment scores for individual genes and molecular pathways based on ENCODE project epigenome data for enhancer-specific histone modification H3K4me1 in five human cell lines. We identified consensus groups of molecular processes that are enriched and deficient in RE-linked H3K4me1 regulation. Results: We calculated H3K4me1 RE-linked enrichment scores for 24,070 human genes and 3095 molecular pathways. We ranked genes and pathways and identified those statistically significantly enriched and deficient in H3K4me1 RE-linked regulation. Conclusion: Non-coding RNA genes were statistically significantly enriched by RE-linked H3K4me1 regulatory modules, thus suggesting their high regulatory evolution rate. The processes of gene silencing by small RNAs, DNA metabolism/chromatin structure, sensory perception/neurotransmission and lipids metabolism showed signs of the fastest regulatory evolution, while the slowest processes were connected with immunity, protein ubiquitination/degradation, cell adhesion, migration and interaction, metals metabolism/ion transport, cell death, intracellular signaling pathways.

Distinct Traits of Structural and Regulatory Evolutional Conservation of Human Genes with Specific Focus on Major Cancer Molecular Pathways

“…Upon insertion into a new site of the genome, RE copy is normally epigenetically silenced because its potential transcriptional and regulatory activities can be deleterious for the regulatory profile of the neighboring genes [12]. However, this can change over time when the removal of epigenetic blocks may co-opt REs or parts of their sequences as the new regulatory elements that take part in the control of gene expression, thus contributing to the emergence of new adaptive mechanisms [13]. Widespread functional domestication of the REs in the genomic site is the marker of its faster regulatory evolution and vice versa [14][15][16].…”

“…For all of those types of regulatory elements, the RetroSpect method makes it possible to calculate relative and absolute metrics of RE-linked regulatory enrichment for both individual genes and the whole intracellular molecular pathways [13]. In RetroSpect, relative retroelement enrichment scores for individual genes are reflected by NGRE value (normalized gene RE-linked enrichment score).…”

“…In RetroSpect, relative retroelement enrichment scores for individual genes are reflected by NGRE value (normalized gene RE-linked enrichment score). For the assessment of molecular pathways, NPII (normalized pathway involvement index) values are calculated, which reflect relative retroelement enrichment scores for the whole molecular pathways [13,19,20].…”

“…In the previous Retrospect applications [13,19,20], the most quickly evolving pathways and molecular processes were identified from the regulatory perspective in the human lineage, which were connected with adaptive immunity, RNA interference, sensory perception, sexual reproduction, lipids metabolism, detoxication of toxins, and other processes. In turn, the most slowly evolving processes from the gene regulation point of view dealt with ribosome biogenesis and protein biosynthesis, major transcriptional mechanisms, embryo development, and fundamental intracellular signaling pathways.…”

FNC: An Advanced Anticancer Therapeutic or Just an Underdog?

“…The expression of retrotransposons and HERVs is tightly controlled in a normal cell with most of the elements being transcriptionally repressed ( 11 ). However, in cancer cells due to an overall deregulated epigenetic and transcriptional control, there is a strong transcriptional reactivation of retrotransposons and HERVs, which also play a role of major genomic regulatory elements ( 12 ). Many cancer types were shown to be associated with the reactivation of retrotransposons and HERVs: breast cancer ( 13 ), prostate cancer ( 14 ), melanoma ( 15 ), ovarian cancer ( 16 ), hepatocelular carcinoma ( 17 ), germ cell tumors ( 18 ), renal cell carcinoma ( 19 , 20 ), leukemia ( 21 ), glioblastoma ( 22 ), and osteosarcoma ( 23 ).…”