HMGXB4 Targets Sleeping Beauty Transposition to Vertebrate Germinal Stem Cells

Transposons are parasitic genetic elements that frequently hijack key cellular processes of the host. HMGXB4 is a Wnt signalling-associated HMG-box protein, previously identified as a transcriptional regulating host factor of Sleeping Beauty (SB) transposition. Here, we establish that HMGXB4 is highly expressed from the zygote stage, and declines after transcriptional genome activation. Nevertheless, HMGXB4 is activated by its own promoter at 4-cell stage, responding to the parental-to-zygotic transition, marks stemness, and maintains its expression during germ cell specification. The HMGXB4 promoter is located at an active chromatin domain boundary. As a vertebrate-specific modulator of SETD1A and NuRF complexes, HMGXB4 links histone H3K4 methyltransferase- and ATP-dependent nucleosome remodelling activities. The expression of HMGXB4 is regulated by the KRAB-ZNF/TRIM28 epigenetic repression machinery. A post-transcriptional modification by SUMOylation diminishes its transcriptional activator function and regulates its nucleolar trafficking. Collectively, HMGXB4 positions SB transposition into an elaborate stem cell-specific transcriptional regulatory mechanism that is active during early embryogenesis and germline development, thereby potentiating heritable transposon insertions in the germline.