Model. ERVs recruit KZFPs, TRIM28, SETDB1, DNMT3A/B, and the H3.3/ATRX/DAXX complex. FAM208A also binds to ERVs and is known to interact with H3K9me3 through MPHOSPH8. FAM208A binding spreads through chromatin and overlaps H3K9me3, suggesting HUSH uses H3K9me3 as a platform on which to spread. TRIM28 is required to repress ERVs but FAM208A is not, likely because it is redundant at these sites of dense H3K9me3. Young L1s, in contrast, reside in “leaky heterochromatin” or part euchromatin, which exhibits weak TRIM28 and FAM208A binding and low levels of H3K9me3 and DNA methylation. Both TRIM28 and FAM208A exert nonredundant roles at young L1s. These sites are also rich in new and tissue-specific genes and are flanked by upstream sense LTRs. This suggests that genes may hijack repeats and incomplete epigenetic repression to rewire their expression patterns.
