Overview of transcriptional silencing mechanisms acting at different ERV families and the effect of chromatin factor depletion on mESC fate. (A) The mechanism of transcriptional silencing of class I and II ERVs is distinct from that acting on the class III ERV MERVL. KAP1 is recruited to numerous class I and II ERVs, including IAP and MMERVK10C elements, via an interaction between the RBCC domain of KAP1 and the KRAB box of KRAB-ZFPs, which presumably bind directly to specific sequences within these ERVs. The SUMOylated bromodomain of KAP1 recruits SETDB1, which deposits the repressive H3K9me3 mark. MERVL elements in contrast, are bound by G9a and marked by H3K9me2 in a G9a-dependent manner. As these ERVs are upregulated in the absence of G9a or GLP, we propose that the G9a/GLP complex directly regulates MERVL expression via deposition of H3K9me2. (B) Depletion of specific chromatin factors, including KAP1 and HP1 proteins, may promote MERVL expression via indirect effects. MERVL transcripts and MERVL-driven genic transcripts are abundant at the 2C embryonic stage, but are rapidly depleted at subsequent stages, including the blastocyst, from which mESCs are derived. While a small fraction of wt mESCs continually enter a transient state associated with expression of multiple 2C-specific genes, the percentage of these cells increases dramatically in mESCs depleted of KAP1, G9a/GLP and LSD1 [11, 12]. One or more of the 2C-specific genes commonly induced in these cells as well as in HP1α and HP1β KO mESCs may indirectly promote transcription of MERVL elements and MERVL LTR-driven genes.