Background: Transposons are selfish genetic elements that self-reproduce in host DNA. They were active during evolutionary history and now occupy almost half of mammalian genomes. Close insertions of transposons reshaped structure and regulation of many genes considerably. Co-evolution of transposons and host DNA frequently results in the formation of new regulatory regions. Previously we published a concept that the proportion of functional features held by transposons positively correlates with the rate of regulatory evolution of the respective genes. Methods: We ranked human genes and molecular pathways according to their regulatory evolution rates based on high throughput genome-wide data on five histone modifications (H3K4me3, H3K9ac, H3K27ac, H3K27me3, H3K9me3) linked with transposons for five human cell lines. Results: Based on the total of approximately 1.5 million histone tags, we ranked regulatory evolution rates for 25075 human genes and 3121 molecular pathways and identified groups of molecular processes that showed signs of either fast or slow regulatory evolution. However, histone tags showed different regulatory patterns and formed two distinct clusters: promoter/active chromatin tags (H3K4me3, H3K9ac, H3K27ac) vs. heterochromatin tags (H3K27me3, H3K9me3). Conclusion: In humans, transposon-linked histone marks evolved in a coordinated way depending on their functional roles.

Background: Retroelements (REs) are transposable elements occupying ~40% of the human genome that can regulate genes by providing transcription factor binding sites (TFBS). RE-linked TFBS profile can serve as a marker of gene transcriptional regulation evolution. This approach allows for interrogating the regulatory evolution of organisms with RE-rich genomes. We aimed to characterize the evolution of transcriptional regulation for human genes and molecular pathways using RE-linked TFBS accumulation as a metric. Methods: We characterized human genes and molecular pathways either enriched or deficient in RE-linked TFBS regulation. We used ENCODE database with mapped TFBS for 563 transcription factors in 13 human cell lines. For 24,389 genes and 3124 molecular pathways, we calculated the score of RE-linked TFBS regulation reflecting the regulatory evolution rate at the level of individual genes and molecular pathways. Results: The major groups enriched by RE regulation deal with gene regulation by microRNAs, olfaction, color vision, fertilization, cellular immune response, and amino acids and fatty acids metabolism and detoxication. The deficient groups were involved in translation, RNA transcription and processing, chromatin organization, and molecular signaling. Conclusion: We identified genes and molecular processes that have characteristics of especially high or low evolutionary rates at the level of RE-linked TFBS regulation in human lineage.

Background: Overall survival of advanced colorectal cancer (CRC) patients remains poor, and gene expression analysis could potentially complement detection of clinically relevant mutations to personalize CRC treatments. Methods: We performed RNA sequencing of formalin-fixed, paraffin-embedded (FFPE) cancer tissue samples of 23 CRC patients and interpreted the data obtained using bioinformatic method Oncobox for expression-based rating of targeted therapeutics. Oncobox ranks cancer drugs according to the efficiency score calculated using target genes expression and molecular pathway activation data. The patients had primary and metastatic CRC with metastases in liver, peritoneum, brain, adrenal gland, lymph nodes and ovary. Two patients had mutations in NRAS, seven others had mutated KRAS gene. Patients were treated by aflibercept, bevacizumab, bortezomib, cabozantinib, cetuximab, crizotinib, denosumab, panitumumab and regorafenib as monotherapy or in combination with chemotherapy, and information on the success of totally 39 lines of therapy was collected. Results: Oncobox drug efficiency score was effective biomarker that could predict treatment outcomes in the experimental cohort (AUC 0.77 for all lines of therapy and 0.91 for the first line after tumor sampling). Separately for bevacizumab, it was effective in the experimental cohort (AUC 0.87) and in 3 independent literature CRC datasets, n = 107 (AUC 0.84–0.94). It also predicted progression-free survival in univariate (Hazard ratio 0.14) and multivariate (Hazard ratio 0.066) analyses. Difference in AUC scores evidences importance of using recent biosamples for the prediction quality. Conclusion: Our results suggest that RNA sequencing analysis of tumor FFPE materials may be helpful for personalizing prescriptions of targeted therapeutics in CRC.

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.

Human retroelements (REs), which comprise approximately 40% of the genome, have played a pivotal role in the evolution of key molecular processes, such as placental development, by introducing novel regulatory elements near host gene promoters and enhancers. Despite their genomic abundance and regulatory influence, the functional trajectories of REs remain poorly understood. Here, leveraging ChIP-seq profiles of histone modifications (H3K4me1, H3K4me3, H3K9ac, H3K27ac, H3K27me3, and H3K9me3) from five human cell lines deposited in the ENCODE database, we systematically ranked the regulatory impact of REs across 25,075 human genes. Gene sets enriched for promoter- and enhancer-associated RE-linked regulatory sites were identified. Consensus gene sets across cell lines were found to be associated with pathways involved in cancer progression, specifically chronic myeloid leukemia and small cell lung cancer, as well as with host defense responses to infection with human T-cell lymphotropic virus type 1. These findings provide new insights into recent human evolution and highlight the ongoing influence of selfish genetic elements on genome regulation and disease susceptibility.

For a quarter of a century transposable elements have been recognized as a major component of the human genome, comprising 46.1% according to recent estimates, and as key drivers of regulatory innovation as well as participants in an ongoing evolutionary arms race with host defense systems. Using the newly released T2T ENCODE dataset, we quantified the epigenetic impact of 3.7 million transposable elements across evolutionary time by analyzing seven epigenomic modalities in twelve human cell lines, spanning six transposon classes, 44 families, and 1,122 subfamilies. We show that SVA elements exhibit the strongest signatures of the arms race, characterized by progressive escape from H3K9me3-mediated heterochromatinization accompanied by increased acquisition of CTCF binding and enhancer-associated chromatin marks. Among Alu elements, the AluYb8 and AluYb9 subfamilies display age-dependent accumulation of CTCF binding, while seven LTR subfamilies (HERV16-int, MER11C, LTR43-int, HERVE-int, LTR22C, LTR5_Hs, HERVIP10FH-int) demonstrate dynamic evolutionary behavior within active chromatin, H3K9me3 chromatin and CTCF contexts. We further evaluated the relative contribution of distinct epigenomic modalities to the host–transposable element conflict and found that transposon-driven evolution is dominated by evasion of host-imposed heterochromatinization primarily at H3K9me3 and secondarily at H3K27me3, together with progressive invasion into CTCF-rich regions. In contrast, enhancer, promoter, and H3K36me3 marks appear to play more limited roles. Collectively, these findings deepen our insight into the coevolutionary epigenomic dynamics between human genome and transposable elements and the associated processes driving regulatory innovation.