HP1β and densely packed chromatin form separate microdomains in mouse ES cells, which are reconfigured upon exit from naive pluripotency

Heterochromatin proteins play a key role in establishing local chromatin structure to control the transcription of target genes. Here we uncover a surprising segregation between regions of high DNA- and high heterochromatin protein 1β (HP1β)-density in mouse ES cells. DNA-low/HP1β-high foci retain freely diffusing HP1β, and form via condensation through a multitude of weak interactions on top of HP1β that is bound stably to chromatin. DNA-high/HP1β-low foci exclude freely diffusing HP1β and display reduced chromatin mobility, suggesting a higher degree of chromatin self-interaction and a more repressive environment. Finally, the two types of environments are intertwined in DNA-high/HP1β-high foci, where HP1β maintains heterochromatin in a more compact yet dynamic chromatin state. During the exit from naive pluripotency HP1β is lost from regions of high DNA density as cells transition through the formative state, which might facilitate the reconfiguration of genome structure accompanying a change in cell state that we observed previously. Subsequently, as cells enter primed pluripotency, canonical heterochromatin is established.