The Rhox gene cluster suppresses germline LINE1 transposition

Long interspersed element class 1 (LINE1) elements are transposable elements that comprise ∼20% of mammalian genomes. Their activity must be tightly controlled or genome integrity will be compromised, leading to DNA damage and cell death. Here, we report that several members of a rapidly evolving X-linked homeobox gene cluster suppress LINE1 transposition. One family member of this Rhox gene cluster—Rhox10—silences LINE1 expression and transposition in the male germline when it is hypomethylated and thus highly susceptible to LINE1 activation. Rhox10 acts by driving the expression of Piwil2, which encodes a key component in the Piwi-interacting RNA pathway. The ability of Rhox genes to suppress LINE1 elements is evolutionarily conserved and perturbed by mutation in infertility patients.