Cooperation between a hierarchical set of recruitment sites targets the X chromosome for dosage compensation

Autor: Lena Annika Street, Lara Heermans Winterkorn, Sarah Elizabeth Albritton, Sevinc Ercan, Anna Lena Kranz
Rok vydání: 2017
Předmět:
Zdroj: eLife, Vol 6 (2017)
eLife
ISSN: 2050-084X
DOI: 10.7554/elife.23645
Popis: In many organisms, it remains unclear how X chromosomes are specified for dosage compensation, since DNA sequence motifs shown to be important for dosage compensation complex (DCC) recruitment are themselves not X-specific. Here, we addressed this problem in C. elegans. We found that the DCC recruiter, SDC-2, is required to maintain open chromatin at a small number of primary DCC recruitment sites, whose sequence and genomic context are X-specific. Along the X, primary recruitment sites are interspersed with secondary sites, whose function is X-dependent. A secondary site can ectopically recruit the DCC when additional recruitment sites are inserted either in tandem or at a distance (>30 kb). Deletion of a recruitment site on the X results in reduced DCC binding across several megabases surrounded by topologically associating domain (TAD) boundaries. Our work elucidates that hierarchy and long-distance cooperativity between gene-regulatory elements target a single chromosome for regulation. DOI: http://dx.doi.org/10.7554/eLife.23645.001
eLife digest The DNA inside living cells is organized in structures called chromosomes. In many animals, females have two X chromosomes, whereas males have only one. To ensure that females do not end up with a double dose of the proteins encoded by the genes on the X chromosome, animals use a process called dosage compensation to correct this imbalance. The mechanisms underlying this process vary between species, but they typically involve a regulatory complex that binds to the X chromosomes of one sex to modify gene expression. Caenorhabditis elegans, for example, is a species of nematode worm in which individuals with two X chromosomes are hermaphrodites and those with one X chromosome are males. In C. elegans, a regulatory complex, called the dosage compensation complex, attaches to both X chromosomes of a hermaphrodite, and reduces the expression of the genes on each by half to match the level seen in the males. Previous research has shown that short DNA sequences, known as motifs, recruit the dosage compensation complex to the X chromosomes. However, these sequences are also found on the other chromosomes and, until now, it was not known why the complex was only recruited to the X chromosomes. Albritton et al. now show the X chromosomes have a ‘hierarchical’ recruitment system. A few sites on the X chromosomes contain clusters of a specific DNA motif, which initiate the process and attract the dosage compensation complex more strongly than other sites. These ‘strong’ recruitment sites are placed across the length of the X chromosomes and cooperate with several ‘weaker’ ones located in between. This way, multiple recruitment sites can cooperate over a long distance, while non-sex chromosomes, which have only one or two stronger recruitment sites, do not have thisadvantage. Hierarchy and cooperativity may be general features of gene expression, in which proteins are targeted to chromosomes without the need for having specific motifs at every recruitment site. The way DNA sequences are distributed across the genome may give us clues about their role. Thus, knowing how genomes are structured will help us identify disrupted areas in diseases such as cancer. DOI: http://dx.doi.org/10.7554/eLife.23645.002
Databáze: OpenAIRE
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