Key Takeaways:
- Study reveals cues that guide chromatin remodeling complexes to turn on genes in cells.
- Mutated complexes play a major role in cancer development.
Studies in the lab of Cigall Kadoch, PhD, are shedding new light on how molecular machines called BAF chromatin remodeling complexes “go where they need to go” within the DNA genome of cells, binding to specific locations to govern which genes turn on and off to orchestrate cell functions.
The findings, described in the journal Science, are the latest advance from the Kadoch lab in unraveling the workings of the chromatin regulatory system, which is critical in determining the timing, amount, and location of proteins made by the cell. Her research team focuses on a specific component of this system, the BAF chromatin remodeling complexes, because they are frequently mutated in cancer, disrupting normal gene expression and triggering uncontrolled growth of cells. Already, an improved understanding of BAF complexes achieved by Kadoch and colleagues is leading to development of several new drug candidates to attack cancer.
Chromatin is a combination of DNA and proteins that allows long DNA molecules to compact into denser structures called nucleosomes. A nucleosome is a spool-like structure consisting of two turns of DNA wrapped around a set of eight proteins called histones. This packing allows all of a cell’s DNA –=— which, if stretched out, would form a thin thread about six feet long — to be squeezed into the cell’s nucleus, the size of which is less than the diameter of a pinhead.
Chromatin remodeling complexes are named as such because they temporarily move the coils of DNA around nucleosomes: this makes segments of DNA accessible to the cell’s machinery, which can then read genetic instructions to initiate the production of proteins. What hasn’t been well understood, Kadoch says, is how “cues” contained in the nucleosomes — the chromatin “landscape” — help guide the chromatin remodeling complexes “to get where they need to go” to turn genes on and off.
“It has been a long-held goal to understand the direct determinants that tell the remodeling complexes to go to this nucleosome but not that nucleosome,” Kadoch says.
In a set of high-throughput experiments, Kadoch and her colleagues isolated three different types of BAF chromatin remodeling complexes from mammalian cells. Then they used a library of nucleosomes containing histones with a variety of post-translational modifications, mutations, and other variations which might affect how the remodeling complexes engaged with and subsequently remodeled them.
Because they used a clever DNA-barcoding approach, which allowed the experiment to be done in a massively parallel way for all hundred-plus nucleosomes, Kadoch’s team effectively collected over 25,000 remodeling measurements reporting on how the BAF chromatin remodeling complexes responded to the diverse chromatin landscape of nucleosomes. The experiments uncover “principles that shape the genomic binding and activities of a major chromatin remodeler complex family,” say the investigators. Those principles underly the guidance system of chromatin that directs remodeler complexes to the appropriate locations.
“This suggests a new paradigm that the histone code itself can ‘tune’ the placement and function of remodeling complexes,” adds Kadoch.
The well-appreciated histone code hypothesis suggests that translation of genetic information encoded in DNA is partly controlled by chemical modifications of histone proteins within the nucleosomes. “This is the first step toward understanding how the large BAF complexes actually interact with DNA and how they localize to specific sites across our genomes. These complexes play major roles in cancer. As such, these findings suggest new ways to chemically inhibit specific targeting or specific functions of the remodeling complexes” as potential cancer therapies.