Pericentric heterochromatin state during the cell cycle controls the histone variant composition of centromeres

Abstract

Correct chromosome segregation requires a unique chromatin environment at centromeres and in their vicinity. Here, we address how the deposition of canonical H2A and H2A.Z histone variants is controlled at pericentric heterochromatin (PHC). While in euchromatin newly-synthesized H2A and H2A.Z are deposited throughout the cell cycle, we reveal two discrete waves of deposition at PHC: during mid-late S phase in a replication-dependent manner for H2A, and during G1 phase for H2A.Z. This G1 cell cycle restriction is lost when heterochromatin features are altered, leading to accumulation of H2A.Z at the domain. Interestingly, compromising PHC integrity also impacts neighboring centric chromatin, increasing the amount of centromeric CENP-A without changing its deposition timing. We conclude that the higher-order chromatin structure at the pericentric domain influences dynamics at the nucleosomal level within centromeric chomatin. The two different modes of rearrangement of the former during the cell cycle provide distinct opportunities to replenish one or the other H2A variant, highlighting PHC integrity as a potential signal to regulate the deposition timing and stoichiometry of histone variants at the centromere.