The <i>Rhox</i> gene cluster suppresses germline <i>LINE1</i> transposition.

Abstract

Transposable elements (TEs) are mobile sequences that engender widespread mutations and thus are a major hazard that must be silenced. The most abundant active class of TEs in mammalian genomes is long interspersed element class 1 (<i>LINE1</i>). Here, we report that <i>LINE1</i> transposition is suppressed in the male germline by transcription factors encoded by a rapidly evolving X-linked homeobox gene cluster. <i>LINE1</i> transposition is repressed by many members of this RHOX transcription factor family, including those with different patterns of expression during spermatogenesis. One family member-RHOX10-suppresses <i>LINE1</i> transposition during fetal development in vivo when the germline would otherwise be susceptible to <i>LINE1</i> activation because of epigenetic reprogramming. We provide evidence that RHOX10 suppresses LINE transposition by inducing <i>Piwil2</i>, which encodes a key component in the Piwi-interacting RNA pathway that protects against TEs. The ability of RHOX transcription factors to suppress <i>LINE1</i> is conserved in humans but is lost in <i>RHOXF2</i> mutants from several infertile human patients, raising the possibility that loss of <i>RHOXF2</i> causes human infertility by allowing uncontrolled <i>LINE1</i> expression in the germline. Together, our results support a model in which the <i>Rhox</i> gene cluster is in an evolutionary arms race with TEs, resulting in expansion of the <i>Rhox</i> gene cluster to suppress TEs in different biological contexts.