Academic journal article Genetics

Distinct Roles of Chromatin Insulator Proteins in Control of the Drosophila Bithorax Complex

Academic journal article Genetics

Distinct Roles of Chromatin Insulator Proteins in Control of the Drosophila Bithorax Complex

Article excerpt

THE eukaryotic genome is folded extensively to fi t inside the cell nucleus. The folding patterns vary between individual cells but certain conformations occur more frequently. In some cases, the likelihood of acquiring a particular conformation is linked to activation or repression of specific genes. Such links are especially important for complex loci in which multiple regulatory elements are positioned tens of thousands of base pairs (kb) away from their target promoters. The Drosophila bithorax complex is one of the best studied complex loci. The bithorax complex consists of three evolutionarily conserved homeotic genes Ubx, abd-A, and Abd-B that encode transcription factors and specify anterior-posterior identity of the last thoracic and all abdominal segments of the fly (Maeda and Karch 2006). Segment-specific expression of the bithorax complex genes is controlled by distal transcriptional enhancers and polycomb/trithorax response elements (PRE/TREs). The correct function of enhancers and PREs/ TREs is further orchestrated by chromatin insulator elements that modulate the topology of the bithorax complex by mechanisms that are not well understood.

Chromatin insulator elements were first discovered in Drosophila and later found in vertebrates and plants. They are short (^1 kb) DNA elements that can block ("insulate") transcriptional activation of a promoter by a remote enhancer when interposed between the two. In contrast to transcriptional repression, insulation leaves the promoter transcriptionally competent so it is free to engage with other enhancers as long as those are not separated from the promoter by the insulator element.

The function of insulator elements depends on associated chromatin insulator proteins and here most of what we know comes from studies in Drosophila. Based on their biochemical and functional properties, the known Drosophila insulator proteins can be divided in three groups. The first group consists of nine sequence-specificDNAbindingproteins: Su(Hw), CTCF, BEAF-32, Ibf1, Ibf2, Pita, ZIPIC (also known as CG7928), Dwg (also known as Zw5), and GAF (the product of Trithorax-like gene) (Geyer and Corces 1992; Zhao et al. 1995; Gaszner et al. 1999; Schweinsberg et al. 2004; Moon et al. 2005; Cuartero et al. 2014; Maksimenko et al. 2015; Wolle et al. 2015). The second group includes Cp190 and multiple protein isoforms encoded by the mod(mdg4) gene (Dorn et al. 2001; Pai et al. 2004; Van Bortle et al. 2012). The Cp190 and Mod(mdg4) proteins have no sequence specificity and may not be able to bind DNA directly. They can, however, mediate homotypic and heterotypic protein-protein interactions via their BTB/POZ (Broad complex, Tramtrack, Bric-a-brac)/(Poxvirus and Zinc finger) domains. The third group includes biochemically diverse proteins: Elba1, Elba2, Elba3, and Shep (Aoki et al. 2012; Matzat et al. 2012). Though not required for enhancer blocking, these proteins appear to modulate the enhancer-blocking ability of insulator elements in a tissue- or stage-specific manner. Of all Drosophila insulator proteins, only CTCF has a clear ortholog in mammals (Baniahmad et al. 1990; Lobanenkov et al. 1990). Multiple lines of evidence indicate that insulator proteins act as multisubunit complexes (Matzat and Lei 2014). In addition, genomic mapping shows that insulator proteins bind chromatin in distinct combinations (Negre et al. 2010; Schwartz et al. 2012; Cuartero et al. 2014; Maksimenko et al. 2015). Importantly, only certain combinations of insulator proteins make these elements capable of blocking enhancer- promoter communications, suggesting that these proteins have additional unrelated functions.

Mechanisms by which insulator elements block enhancer- promoter communications are not yet clear. The most popular hypothesis suggests that insulator elements interact with each other and form chromatin loops that compete with chromatin looping involved in enhancer-promoter communication. Supporting this notion, certain insulator protein binding sites are enriched at bases of chromatin loops detected by genome-wide chromatin conformation capture (Hi-C) analysis (Rao et al. …

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