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How Chromatin Remodelers Open Genetic Vaults

2016-02-10
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    Genes cannot be expressed if they remain inaccessible, locked within tightly packed chromatin. However, even deeply buried genes can be exposed to transcription machinery. They key? Chromatin Remodeling Enzymes. But it has been unclear whether these enzymes act like skeleton keys or are more specific, targeting specific nucleosomes to regulate transcription.


    To investigate the safe-cracking ways of remodeler enzymes, scientists at the University of Paris-Sud and Penn State University assembled genome-wide remodeler–nucleosome interaction profiles for eight remodeler enzymes in mouse embryonic stem (ES) cells. They found that each remodeler binds at specific nucleosome positions relative to the start of genes, and that the same remodeler can act as a positive or negative regulator of transcription depending on the activity of the gene it binds.


    These results appeared February 4 in the print edition of the journal Nature, in an article entitled “Genome-wide nucleosome specificity and function of chromatin remodelers in ES cells.” The article explained that the remodelers—Chd1, Chd2, Chd4, Chd6, Chd8, Chd9, Brg1, and Ep400—bind one or both full nucleosomes that flank micrococcal nuclease (MNase)-defined nucleosome-free promoter regions (NFRs), where they separate divergent transcription.


    “We knew that the compaction into chromatin makes genes inaccessible to the cellular machinery necessary for gene expression, and we also knew that enzymes opened up the chromatin to specify which genes were accessible and could be expressed in a cell,” said B. Franklin Pugh, a professor of biochemistry and molecular biology at Penn State University and one of the two corresponding authors of the paper. “Until now, however, we didn’t know the mechanism by which these enzymes functioned.”


    The researchers first mapped the location of several “chromatin-remodeler enzymes” across the entire genome of the embryonic stem cells of the mouse. The mapping showed that remodeler enzymes bind to particular nucleosome “beads” at the sites along the wrapped-up DNA that are located just before the gene sequence begins. These sites are important because they are the locations where the process of expressing genes begins—where other proteins required for gene expression team up for the process of turning a gene on.


    “These remodelers bind one or both full nucleosomes that flank micrococcal nuclease (MNase)-defined nucleosome-free promoter regions (NFRs), where they separate divergent transcription,” indicated the authors of the Nature article. “RNA polymerase II…navigates hundreds of base pairs of altered chromatin in the sense direction before encountering a MNase-resistant nucleosome at the 3′ end of the NFR.”


    The researchers then tested how the chromatin-remodeler enzymes affect gene expression by reducing the amount of each of these enzymes in embryonic stem cells. The scientists found that some chromatin-remodeler enzymes promote gene expression, some repress gene expression, and some can do both.


    “Transcriptome analysis after remodeler depletion reveals reciprocal mechanisms of transcriptional regulation by remodelers,” the authors wrote. “Whereas at active genes, individual remodellers have either positive or negative roles via altering nucleosome stability, at polycomb-enriched bivalent genes the same remodellers act in an opposite manner.”


    “The correct expression of genes is necessary to define the identity and function of different types of cells in the course of embryonic development and adult life,” concluded Dr. Pugh. “Chromatin-remodeler enzymes help each cell type accurately express the proper set of genes by allowing or blocking access to the critical section of DNA at the beginning of genes.”

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