Histone hypoacetylation is required to maintain late replication timing of constitutive heterochromatin

Abstract

The replication of the genome is a spatio-temporally highly organized process. Yet, its flexibility throughout development suggests that this process is not genetically regulated. However, the mechanisms and chromatin modifications controlling replication timing are still unclear. We made use of the prominent structure and defined heterochromatic landscape of pericentric regions as an example of late replicating constitutive heterochromatin. We manipulated the major chromatin markers of these regions, namely histone acetylation, DNA and histone methylation, as well as chromatin condensation and determined the effects of these altered chromatin states on replication timing. Here, we show that manipulation of DNA and histone methylation as well as acetylation levels caused large-scale heterochromatin decondensation. Histone demethylation and the concomitant decondensation, however, did not affect replication timing. In contrast, immuno-FISH and time-lapse analyses showed that lowering DNA methylation, as well as increasing histone acetylation, advanced the onset of heterochromatin replication. While dnmt1−/− cells showed increased histone acetylation at chromocenters, histone hyperacetylation did not induce DNA demethylation. Hence, we propose that histone hypoacetylation is required to maintain normal heterochromatin duplication dynamics. We speculate that a high histone acetylation level might increase the firing efficiency of origins and, concomitantly, advances the replication timing of distinct genomic regions.

Kaposi's Sarcoma-Associated Herpesvirus-Encoded LANA Contributes to Viral Latent Replication by Activating Phosphorylation of Survivin

“…Previous studies showed that histone hypoacetylation is associated with replication timing of chromatin (68). Therefore, we investigated whether histone H3 acetylation and survivin have any effect on the KSHV genome copy number.…”

DNA replication timing during development anticipates transcriptional programs and parallels enhancer activation

“…Acetylation of multiple sites on H3 and H4 histones was previously shown to influence origin activity, and hypoacetylation of these histones is thought to be necessary to maintain late replication timing (Unnikrishnan et al 2010;Casas-Delucchi et al 2012). Furthermore, there is evidence that replication timing itself can influence histone acetylation levels, and thereby transcription and nucleosome structure (Zhang et al 2002;Lande-Diner et al 2009).…”

Multiple Functions of Kip-Related Protein5 Connect Endoreduplication and Cell Elongation

“…Indeed, 75% of KRP5 targets are in heterochromatin regions, suggesting that KRP5 may modulate chromatin organization. Many lines of evidence link chromatin structure and DNA replication: replication timing requires specific chromatin marks (Casas-Delucchi et al, 2012), and recently, the chromatin factor CAF-1 has been implicated not only in the control of meristem structure but also in the control of genome replication at several stages of development (Exner et al, 2006). Another example is that mutations in the genes encoding the two homologous H3K27 monomethyltransferases ATXR5 and ATXR6 lead to the rereplication of specific genomic portions.…”