NIH Research Festival
FARE Award Winner
Retroviruses have been invading mammalian germ lines for millions of years, accumulating in the form of endogenous retroviruses (ERVs) that account for nearly one-tenth of the human genome. To protect their genomic integrity, mammals have developed a number of anti-retroviral defense mechanisms that include epigenetic repression of ERVs during development. However, the adaptive cellular factors that recognize and repress ERVs and other parasitic DNA elements during development have remained elusive. We have recently shown that ZFP809, a member of the KRAB-ZFP family, initiates silencing of a defined subset of ERVs and a handful of ERV-associated host genes in a sequence-specific manner via recruitment of heterochromatin inducing complexes during early development. Here, we determine genome-wide binding profiles of several previously uncharacterized murine KRAB-ZFPs. We show that the majority of the screened candidates bind to defined target sequences within distinct ERV groups. The identified KRAB-ZFP target sequences in ERVs correlate with binding sites of epigenetic corepressors and induce transcriptional repression of reporter genes. Finally, we describe the case of two closely related KRAB-ZFPs that arose from recent gene duplication and, despite sharing a large proportion of their DNA binding domain, show differential DNA binding specificities, either to non-retroviral gene promoters or ERVs. In sum, these data strongly support the hypothesis that possibly hundreds of KRAB-ZFPs evolved, and are still evolving, in response to germ-line colonization events by ERVs and other transposable elements.
Scientific Focus Area: Molecular Biology and Biochemistry
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