Academic journal article Genetics

Drosophila Heterochromatin Stabilization Requires the Zinc-Finger Protein Small Ovary

Academic journal article Genetics

Drosophila Heterochromatin Stabilization Requires the Zinc-Finger Protein Small Ovary

Article excerpt

While gene activation by specific transcription factors is important during development, coordinated repression is also an essential process (Beisel and Paro 2011). Gene silencing represents an effective method to ensure that genes and transposons are not inappropriately activated. Gene repression can be carried out on a regional basis to inactivate large blocks of the genome by the formation of heterochromatin (Elgin and Reuter 2013). Heterochromatization relies on the dense, higher-order packing of nucleosomes, which compete for DNA binding with transcription factors (Jenuwein and Allis 2001; Kouzarides 2007; Lorch and Kornberg 2017). Once heterochromatin forms, it is maintained by a set of largely conserved proteins.

In Drosophila, heterochromatin formation occurs early during embryogenesis, where it is targeted to large blocks of repetitive DNA sequences (Elgin and Reuter 2013), including both mobile transposons and immobile mutated derivatives (Vermaak and Malik 2009). Active suppression through condensation into heterochromatin prevents the mobilization of transposons. Nevertheless, some regulated transcription of heterochromatic sequences is required for normal cellular functions. For example, the telomeres of Drosophila are maintained by the transcription and transposition of mobile elements from heterochromatic sites (Mason et al. 2008), and actively expressed histone and ribosomal RNA genes are located within heterochromatic regions (Yasuhara and Wakimoto 2006). Thus, heterochromatin serves many distinct functions and must be tightly regulated to coordinate gene expression.

The spreading of heterochromatin results in an interesting phenotype in Drosophila, whereby genes near a heterochromatin-euchromatin boundary may become repressed (Elgin and Reuter 2013). For example, when white+ (w+) transgenes are located at such a boundary, the eye can have a mottled appearance where some ommatidia express pigment while others do not. This phenomenon is known as position-effect variegation (PEV). Mutations that suppress PEV {i.e., suppressors of variegation [Su(var)]} identify genes that promote heterochromatin formation. Indeed, many of the genes required for heterochromatin function were identified in PEV modifier screens (Reuter et al. 1986; Eissenberg et al. 1990; Brower-Toland et al 2009). Reducing heterochromatization by Su(var) mutations results in derepression of gene expression at the edges of heterochromatin blocks, suggesting that the boundaries between repressed and active chromatin expand and contract (Reuter and Spierer 1992; Weiler and Wakimoto 1995). For example, the highly conserved Heterochromatin Protein 1a (HP1a), encoded by Su(var)205, is critical for heterochromatin formation and function (Ebert et al. 2006); mutants show strong suppression of variegation (James and Elgin 1986; Eissenberg et al. 1990; Clark and Elgin 1992). Similarly, HP1a is also required to repress the expression of transposons (Vermaak and Malik 2009). HP1a may also be required for preventing the misexpression of large cohorts of genes, such as those normally expressed in specialized cell types (Greil et al. 2003; Figueiredo et al. 2012). Indicative of its central role in heterochromatization, HP1a associates with newly formed heterochromatin in the Drosophila embryo and is thought to be found in all cells throughout the life of the animal (James etal. 1989).

Both the formation and relaxation of heterochromatin depend primarily on histone modifications. Heterochromatin is thought to be nucleated by HP1a binding to di- and trimethylated Histone 3 Lys9 (H3K9me) and spread by multimerization of HP1a over blocks of chromatin (Nakayama et al. 2001; Canzio et al. 2011). In Drosophila, the methyltransferases Eggless (Egg)/SETDB1 and Su(var)3-9 catalyze the addition of methyl groups at H3K9 (Clough et al. 2007; Yoon et al. 2008), but there may be additional ways to bind HP1a to chromatin. Work in Drosophila shows that destruction of the H3K9me site recognized by HP1a (via a K9 to R9 mutation) reduces, but does not abolish, HP1a binding and heterochromatin formation (Penke et al. …

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