Abstract
H3 lysine 9 trimethylation (H3K9me3) is a histone posttranslational modification (PTM) that has emerged as hallmark of pericentromeric heterochromatin. This constitutive chromatin domain is composed of repetitive DNA elements, whose transcription is differentially regulated. Mammalian cells contain three HP1 proteins, HP1α, HP1β and HP1γ These have been shown to bind to H3K9me3 and are thought to mediate the effects of this histone PTM. However, the mechanisms of HP1 chromatin regulation and the exact functional role at pericentromeric heterochromatin are still unclear. Here, we identify activity-dependent neuroprotective protein (ADNP) as an H3K9me3 associated factor. We show that ADNP does not bind H3K9me3 directly, but that interaction is mediated by all three HP1 isoforms in vitro. However, in cells ADNP localization to areas of pericentromeric heterochromatin is only dependent on HP1α and HP1β. Besides a PGVLL sequence patch we uncovered an ARKS motif within the ADNP homeodomain involved in HP1 dependent H3K9me3 association and localization to pericentromeric heterochromatin. While knockdown of ADNP had no effect on HP1 distribution and heterochromatic histone and DNA modifications, we found ADNP silencing major satellite repeats. Our results identify a novel factor in the translation of H3K9me3 at pericentromeric heterochromatin that regulates transcription.
Highlights
The physiological template of genetic information in all eukaryotic cells is chromatin
One factor that had so far not been described in the context of heterochromatin or H3K9me3 was the activity dependent neuroprotector protein, activity-dependent neuroprotective protein (ADNP)
The tubulin-like staining was observed in mitotic NIH3T3 cells where we found ADNP excluded from chromatin from metaphase to telophase (Figure S3)
Summary
The physiological template of genetic information in all eukaryotic cells is chromatin. Functionally different types of chromatin have been described: euchromatin appears less condensed, is thought to have a more ‘‘open’’ conformation, contains the majority of genes, replicates early and throughout S-phase, and is mostly transcriptionally active. Heterochromatin, in contrast, appears condensed with relative even spacing of nucleosomes, is thought to have a more ‘‘closed’’ conformation, comprises few genes, is replicating late in S-phase, and is largely transcriptionally silent Distinct regions of facultative heterochromatin are characteristic for differentiated cells, while constitutive heterochromatin is found in all cells at specific chromosomal territories, namely telomeres, centromeres and pericentromeric regions. The latter are essential for chromosome replication containing repetitive satellite sequences. The exact mechanism(s) by which the activity of these elements is regulated has not been fully elucidated
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