Retroelement—Linked Transcription Factor Binding Patterns Point to Quickly Developing Molecular Pathways in Human Evolution

Abstract

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.

Large-Scale Profiling of Signaling Pathways Reveals a Distinct Demarcation between Normal and Extended Liver Resection

“…After 86% hepatectomy, liver starts to gain weight very slowly, if at all, with its strongest gains toward 48 h. This time point coincides with the hepatocellular mitotic peak, which follows cell cycle entry around 16-20 h post 68% hepatectomy [4]. Mice were sacrificed at 5 time points after hepatectomy (1,8,16,32, and 48 h) and livers were harvested. Immediately, liver tissue (30 mg) was homogenized and total RNA was isolated using TRIzol (Life Technologies, Carlsbad, CA, USA) following on-column DNase treatment (QIAGEN, Hombrechtikon, Switzerland).…”

“…For the functional annotation of the primary gene expression data, we applied our original algorithm termed OncoFinder [5,8]. It enables calculation of the Pathway Activation Strength (PAS), a value that serves as a qualitative measure of pathway activation.…”

“…The applied significance criteria were as follows: differential gene had to meet simultaneously the two conditions, first, gene expression level for the sample must lie outside the tolerance interval (p < 0.05), and second, the value of CNR must differ from 1 considerably, thus being inferior of 0.66 or exceeding 1.5. The discrete value of ARR (activator/repressor role) reflects the functional role of a protein n in the pathway [5,8].…”

“…The intracellular signaling pathways (ISPs) knowledge base developed by SABiosciences was used to determine structures of ISPs (https://www.qiagen.com/us/shop/genes-and-pathways/pathwaycentral/), which were used for OncoFinder, as described previously [5,8]. The OncoFinder software correctly identified ISPs known to be involved in liver regeneration.…”

“…For instance, the Tcta gene, which is short for "T cell leukemia translocation altered gene", is conserved in organisms ranging from Drosophila to humans and encodes a predicted M(r) 12,000 protein without strong homology to any previously reported proteins and expressed ubiquitously in all normal tissues [13]. To put these data in a sensible biological context, we comprehensively analyzed them using OncoFinder [5,8].…”