Abstract
BackgroundMany noncoding genomic loci have remained constant over long evolutionary periods, suggesting that they are exposed to strong selective pressures. The molecular functions of these elements have been partially elucidated, but the fundamental reason for their extreme conservation is still unknown.ResultsTo gain new insights into the extreme selection of highly conserved noncoding elements (HCNEs), we used a systematic analysis of multi-omic data to study the epigenetic regulation of such elements during the development of Drosophila melanogaster. At the sequence level, HCNEs are GC-rich and have a characteristic oligomeric composition. They have higher levels of stable nucleosome occupancy than their flanking regions, and lower levels of mononucleosomes and H3.3, suggesting that these regions reside in compact chromatin. Furthermore, these regions showed remarkable modulations in histone modification and the expression levels of adjacent genes during development. Although HCNEs are primarily initiated late in replication, about 10% were related to early replication origins. Finally, HCNEs showed strong enrichment within lamina-associated domains.ConclusionHCNEs have distinct and protective sequence properties, undergo dynamic epigenetic regulation, and appear to be associated with the structural components of the chromatin, replication origins, and nuclear matrix. These observations indicate that such elements are likely to have essential cellular functions, and offer insights into their epigenetic properties.
Highlights
Genomic DNA is subject to diverse mutations caused by chemicals, replication errors, and mobile genetic elements
Our results indicate the following: highly conserved noncoding elements (HCNEs) intrinsically favor stable nucleosome occupancy at the sequence level; HCNEs reside within nucleosome-enriched and mononucleosome- and H3.3-depleted regions in S2 cells; the chromatin regions around HCNEs undergo significant changes in epigenetic modification during development, and such changes are correlated with the transcription levels of flanking genes; most HCNEs fire later in replication, some serve as early replication origins; and HCNEs are significantly associated with lamina-associated domains (LADs)
The frequency of A and T nucleotides was found to drop sharply at the boundaries of HCNEs and increase smoothly in the surrounding regions (Figure 1B), in a pattern that is conserved across different lineages [20,21]
Summary
Genomic DNA is subject to diverse mutations caused by chemicals, replication errors, and mobile genetic elements. Some noncoding regions show extreme conservation (even more than coding sequences) over very long evolutionary timeframes [2,3]. Mutations in HCNEs have been associated with various diseases, including cancers and neurodevelopmental disorders [9,10,11]. These functions of HCNEs reflect the activities of the DNA-interacting proteins that bind to very short and degenerate DNA sequences within them [12], and are insufficient to explain the invariability of HCNEs ($200 bp) during evolution. The molecular functions of these elements have been partially elucidated, but the fundamental reason for their extreme conservation is still unknown
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