SINE retrotransposons link replication timing with higher-order genome organization by recruiting H2B monoubiquitination to the gene body

The mammalian genome is spatially segregated into euchromatin-associated A and heterochromatin-associated B compartments that replicate early, and late in S-phase respectively. The molecular links connecting higher-order genome organization with replication timing, however, remain unclear. Here, we show that H2Bub (histone H2B lysine 120 monoubiquitination), a transcription-coupled epigenetic mark enriched over the gene body, regulates early replication. Furthermore, enforced recruitment of H2Bub promotes early replication in cis . Consistent with these observations, genetic ablation of RNF20, an E3 ubiquitin ligase that mediates H2Bub deposition, leads to reduced firing of early replication origins and suppression of cellular and embryonic growth. We also find a role of H2Bub for promoting proximal chromatin contacts at the gene body, and in gene-rich A compartments, indicating that H2Bub may connect replication timing with higher-order genome organization. Surprisingly, H2Bub-marked regions in the genome coincide with SINEs (short interspersed nuclear elements). SINE retrotransposon enrichment in transcribed gene bodies correlates with H2Bub levels, indicating that these elements may direct H2Bub deposition at chromatin. Indeed, ectopic insertion of SINEs promotes local recruitment H2Bub. Taken together, our results suggest an unexpected role for SINE retrotransposons in linking higher-order genome organization with replication timing via targeting of the transcription-coupled epigenetic mark H2Bub.