Drosophila H1 Regulates the Genetic Activity of Heterochromatin by Recruitment of Su(var)3-9

Abstract

Eukaryotic genomes harbor transposable elements and other repetitive sequences that must be silenced. Small RNA interference pathways play a major role in their repression. Here, we reveal another mechanism for silencing these sequences in Drosophila. Depleting the linker histone H1 in vivo leads to strong activation of these elements. H1-mediated silencing occurs in combination with the heterochromatin-specific histone H3 lysine 9 methyltransferase Su(var)3-9. H1 physically interacts with Su(var)3-9 and recruits it to chromatin in vitro, which promotes H3 methylation. We propose that H1 plays a key role in silencing by tethering Su(var)3-9 to heterochromatin. The tethering function of H1 adds to its established role as a regulator of chromatin compaction and accessibility.

Independent Biological and Biochemical Functions for Individual Structural Domains of Drosophila Linker Histone H1

“…Our previous findings showed that H1 is essential for fly development beyond the late larval stage and that it is required for normal chromosome architecture (19). Moreover, we found that H1 plays a particularly prominent role in the structure and genetic activity of heterochromatin, where it participates in epigenetic marking and transcriptional silencing of transposable elements through its interaction with the Su(var)3-9 methyltransferase and STAT92E (7,19,42). By generating transgenic fly lines expressing full-length H1 and six different mutant H1 polypeptides, we interrogated its structural domains for their roles in multiple H1-mediated processes in vivo.…”

“…Transcription of these sequences needs to be silenced for genome integrity. We described previously a role for Drosophila H1 in transcriptional repression of these sequences (7). We found that Drosophila H1 and the heterochromatin-specific histone methyltransferase Su(var)3-9 interact and cooperate to mark heterochromatin with H3K9me2, resulting in silencing of the repetitive elements.…”

“…For instance, we have previously observed that the H1 CTD is sufficient for binding to Drosophila STAT92E, which together with H1 coordinates a unique pathway of heterochromatin organization in flies (42). H1 linker histones have been also shown to interact with HP1 (7,24,25). Finally, we reported that Drosophila H1 interacts directly with the heterochromatin-specific histone methyltransferase Su(var)3-9 and cooperates with it to mark heterochromatin with H3K9me2 (7).…”

“…Drosophila melanogaster offers an attractive system for such studies because, in contrast to mammals, it expresses a single linker histone protein during much of its life cycle. H1 is essential for proper development of flies, and it plays key roles in several aspects of chromosome structure and gene regulation (7,19). Here we investigate the functional roles of the three H1 structural domains, the H1 NTD, GD, and CTD, in the roles of H1 in Drosophila development, chromosome structure, and epigenetic regulation.…”

“…H1 also facilitates the folding of chromatin into more compact structures. In addition to these architectural roles, there are now an increasing number of reports describing interactions between H1 linker histones and a variety of other nuclear proteins (6), including functional interactions between H1, histone-modifying enzymes, and DNA methyltransferases that lead to modulation of epigenetic marking of chromatin (7,8). In this context, it is notable that the binding of linker histones to chromatin is highly dynamic, with residence times much shorter than that of the core histones (9).…”