Causes and functional consequences of chromatin evolution

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PROJECT SUMMARY DNA packaging into chromatin mediates chromosome segregation, telomere protection, and genome integrity, among other essential, conserved cellular processes. However, many chromatin proteins are strikingly unconserved—domains and residues evolve rapidly between even closely related species. This paradox of conserved, chromatin-dependent functions supported by fast-evolving chromatin proteins suggests that some essential cellular processes require recurrent innovation. The biological significance of this paradox is poorly understood, and yet aberrant chromatin packaging is a hallmark of cancer, infertility, and aging. We hypothesize that the pervasive rapid evolution of chromatin proteins is driven by the exceptionally rapid evolution of DNA repeats, including transposons and DNA satellites. Specifically, we hypothesize that chromatin proteins and DNA repeats antagonistically coevolve: repetitive DNA evolution imperils essential chromatin functions, triggering reciprocal evolution of chromatin proteins to restore these essential chromatin functions. Repeated bouts of DNA repeat evolution and chromatin protein adaptation result in exquisitely coevolved, species-specific components of the genome. To probe this model of antagonistic coevolution, we conduct evolution-guided functional analysis: we swap into a focal genome a diverged chromatin protein from a closely related species, generating an "evolutionary mismatch" between the contemporary DNA repeats of one species and a contemporary chromatin protein of another species. Upon swapping a diverged version of a transposon-silencing protein into Drosophila melanogaster, we triggered transposon hyper-proliferation and a consequent loss of genome integrity. Upon swapping a diverged version of a DNA satellite-associated protein into D. melanogaster, we similarly triggered a profound loss of genome integrity but through a distinct pathway. Having successfully defined the genome components engaged in antagonistic coevolution during the current funding period, we are now poised to unravel the molecular mechanisms by which DNA repeats imperil essential chromatin biology and the molecular mechanisms by which chromatin proteins mitigate these threats. Leveraging our two established systems, we will probe the evolutionary and functional diversification of two vital chromatin-mediated pathways shaped by coevolution: 1) the regulation of chromatin accessibility at genomic regions vulnerable to transposon insertions and 2) the resolution of DNA entanglements enriched in DNA satellite arrays. Our published and preliminary data also propel our investigations of how antagonistic coevolution reverberates beyond the two embattled parties, triggering secondary coevolutionary dynamics that preserve protein:protein interactions among multiple host chromatin proteins. Using transgenics, cell biology, biochemistry, and classical genetics, we will elucidate the otherwise invisible hazards of DNA repeat evolution and determine how adaptive evolution shapes and reshapes chromatin to preserve vital genome functions.