Extended Data Figure 6: HUSH and MORC2 preferentially bind full-length L1 instances in human ES cells, mouse ES cells and K562 cells.

a, Widespread genomic co-binding of MPP8 and MORC2 in hES cells. Heat map representation of ChIP–seq results at 57,000 genomic loci, centred on MPP8 and MORC2 summits and sorted by MORC2 ChIP–seq signal. Plotted is the normalized ChIP read density from hES cells. b, Heat maps of MORC2/MPP8 ChIP–seq density over the indicated repeat classes, centred and sorted as in a. The HUSH complex and MORC2 bind predominantly to L1 elements in hES cells, in particular to the primate-specific L1P families, suggesting that HUSH- and MORC2-dependent silencing is relevant in many embryonic and somatic cell types. c, L1 families that encompass active L1 copies, such as L1Md-T and L1Md-A, are significantly enriched among MPP8 binding sites in mouse ES cells. L1Md_Gf is also enriched, but not shown owing to the low number of instances. Thus, HUSH-mediated L1 regulation appears to be conserved among species. Of note is that MPP8 is also strongly enriched at IAP elements, a class of murine endogenous retroviruses that remain currently mobile in the mouse genome. d, MPP8 ChIP–seq heat maps in mouse embryonic stem cells featuring retrotransposition-competent L1Md-T, L1Md-A and L1Md-Gf. e, MPP8 preferentially binds full-length L1Md-A and L1Md-T in mouse ES cells. Plotted is the size distribution of the indicated L1 instances that overlap with MPP8 ChIP–seq peaks, or remaining L1s that do not overlap with such ChIP–seq signals. Box plots show median and IQR, whiskers are 1.5 × IQR. f, Aggregate plots of MORC2 (red) and MPP8 (black) ChIP–seq signals over 500 full-length, MPP8-bound L1PAs, centred on the L1 5′ end. g, Aggregate plots of MORC2 (red) and MPP8 (black) ChIP–seq signals on L1Hs (L1PA1). Similar to the binding profile on L1PA (f), MPP8 and MORC2 occupy the whole body of L1Hs, with MORC2 additionally binding L1Hs 5′ UTR. It is to be noted that ChIP–seq fragments are much less likely to be uniquely mapped—and thus removed by the alignment criteria—within the L1Hs non-5′ UTR region, owing to their minimal sequence divergence (Extended Data Fig. 5a).