Abstract
BackgroundDifferent histone post-translational modifications (PTMs) fine-tune and integrate different cellular signaling pathways at the chromatin level. ADP-ribose modification of histones by cellular ADP-ribosyltransferases such as ARTD1 (PARP1) is one of the many elements of the histone code. All 5 histone proteins were described to be ADP-ribosylated in vitro and in vivo. However, the crosstalk between ADP-ribosylation and other modifications is little understood.ResultsIn experiments with isolated histones, it was found that ADP-ribosylation of H3 by ARTD1 prevents H3 methylation by SET7/9. However, poly(ADP-ribosyl)ation (PARylation) of histone H3 surprisingly allowed subsequent methylation of H1 by SET7/9. Histone H1 was thus identified as a new target for SET7/9. The SET7/9 methylation sites in H1.4 were pinpointed to the last lysine residues of the six KAK motifs in the C-terminal domain (K121, K129, K159, K171, K177 and K192). Interestingly, H1 and the known SET7/9 target protein H3 competed with each other for SET7/9-dependent methylation.ConclusionsThe results presented here identify H1.4 as a novel SET7/9 target protein, and document an intricate crosstalk between H3 and H1 methylation and PARylation, thus implying substrate competition as a regulatory mechanism. Thereby, these results underline the role of ADP-ribosylation as an element of the histone code.
Highlights
Different histone post-translational modifications (PTMs) fine-tune and integrate different cellular signaling pathways at the chromatin level
PARylation inhibits SET7/9-dependent methylation of histone H3 adenosine diphosphate (ADP)-ribosylation is a PTM of a wide variety of target proteins, including histones [20,23,26]
Full-length histone H1.4 was not methylated in the presence of plasmid DNA and neither was an H1.4 mutant lacking the C-terminus (ΔCT) (Figure 3A). These results suggested that H1.4 is methylated at the C-terminal domain (CTD), which has been reported to bind to DNA, and that SET7/9 likely methylates soluble H1.4 that is not part of the chromatin structure
Summary
Different histone post-translational modifications (PTMs) fine-tune and integrate different cellular signaling pathways at the chromatin level. All 5 histone proteins were described to be ADP-ribosylated in vitro and in vivo. Histones are nuclear proteins that package and order the DNA into nucleosomes [1]. Two copies of the core histones H2A, H2B, H3 and H4 form the octameric nucleosome core particles [2]. Only one copy of the linker histone H1 is present and stabilizes the DNA, which is wrapped around the core nucleosome [3]. The study described here focuses on histone H1.4, a histone variant that is expressed in somatic cells during S phase. Similar to the core histones, linker histones are subject to extensive post-translational modifications (PTMs), including phosphorylation, methylation and acetylation [9]
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