LINE elements are a reservoir of regulatory potential in mammalian genomes

Abstract

To investigate the mechanisms driving regulatory evolution across tissues, we experimentally mapped promoters, enhancers, and gene expression in liver, brain, muscle, and testis from ten diverse mammals. The regulatory landscape around genes included both tissue-shared and tissue-specific regulatory regions, where tissue-specific promoters and enhancers evolved 5 most rapidly. Genomic regions switching between promoters and enhancers were more common across species, and less common across tissues within a single species. Long Interspersed Nuclear Elements (LINEs) played recurrent evolutionary roles: LINE L1s were associated with tissue-specific regulatory regions, whereas more ancient LINE L2s were associated with tissue-shared regulatory regions and with those switching between promoter 10 and enhancer signatures across species. Our analyses of the tissue-specificity and evolutionary stability among promoters and enhancers reveal how specific LINE families have helped shape the dynamic mammalian regulome. HIGHLIGHTS 15• Tissue-specific regulatory regions evolve faster than tissue-shared • Switching promoter and enhancer regulatory roles is frequent in evolution • LINE L1s contribute to the evolution of tissue-specific regulatory regions • LINE L2s are associated with broad tissue activity and dynamic regulatory signatures 20

Phylogenetic modeling of enhancer shifts in African mole-rats reveals regulatory changes associated with tissue-specific traits

“…In the four study species, promoters show over 80% commonality across tissues (Figure 1C, Figure S1), in line with their general association with gene expression [23,25]. In contrast, liver and heart enhancers in each of the four rodent species are largely distinct, with just under 30% being typically common to both tissues (Figure 1C, Figure S1), consistent with their role as tissue-specific cis-regulators [29,33].…”

“…We next compared the locations and properties of Up and Down elements identified with phylogenetic modeling (Table S3) to regulatory changes inferred by state-of-the-art methods, such as parsimony [33] and differential binding analysis [39] (Figures S4 and S5).…”

“…Nevertheless, we noticed some of the genomic loci previously linked to mole-rat traits are flanked by regulatory elements that cannot be aligned to the mouse genome (Figure S7), which we term non-alignable. Repetitive genomic regions (which are difficult to align across species) have been previously linked to rewiring of regulatory networks [33][34][35]. We thus investigated the genomic properties of nonalignable promoters and enhancers in our study, and their potential contribution to mole-rat specific gene regulation.…”

“…In contrast, lineage-specific elements appear partly compensatory of proximally lost events [27,31] and typically arise in genomic regions with pre-existing regulatory activity [22,32]. Although mammalian adaptations in gene regulation have been linked to the lineage-specific expansion of repetitive elements [33][34][35], identifying the subsets of rapidly-evolving non-coding elements associated with lineage-specific shifts in regulatory activity has proved more challenging -in part due to limitations in comparative approaches for functional genomics data [36,37].…”

Enhancer Pleiotropy, Gene Expression, and the Architecture of Human Enhancer–Gene Interactions

“…We demonstrated that enhancers primarily act in a tissue-specific manner; highly pleiotropic enhancers were rare, constituting <1% of all putative enhancers across the examined tissues. Notably, recent comparative studies between distant mammalian species have indicated that enhancers tend to be tissue- and species-specific ( Villar et al 2015 ; Roller et al 2020 ). Despite the extreme skew toward tissue-specific enhancer activity, several notable genomic characteristics are positively correlated with increasing enhancer pleiotropy.…”