Transcriptional regulators can change the way chromatin loops group together
Something like the image above is probably what comes to mind first when you hear ‘chromatin structure’. In reality, DNA spends only a small portion of time in these tightly coiled chromosomes. Most chromatin within cells lies in diffuse strands within nuclei. Mapping the locations of genes on these strands, scientists have found that chromatin containing more actively expressed genes tends to cluster together, as do chromatin strands containing inactive genes. Now, two recent papers show that these specific arrangements of chromatin may hold clues to developing targeted drugs for diseases like cancer.
A PNAS paper by Rickman et al. describes the impact of increasing the expression of ERG, an oncogenic transcriptional regulator on the 3-dimensional clusters formed by chromatin in cancer cells. Fusions of the ERG gene resulting in increased expression are very common in prostate cancer and associated with changes in the activity of hundreds of genes across the tumor genome. The scientists transformed the prostate cancer cell line RWPE-1 to overexpress the ERG protein, and mapped changes in interactions of chromatin throughout the genome.
They found that cells over-expressing ERG showed specific, consistent changes in the 3D organization of chromatin. These changes were associated with different expression of genes in the re-organized regions. For example, ERG-overexpressing cells showed a loss of interaction for two genes, TFF3 and TMPRSS2 relative to a GFP-overexpressing cell line. Adding the ERG protein externally to this control cell line also induced a loss of interaction of these two genes, both of which are ERG targets. TMPRSS2 is also one of the most common fusion partners for ERG in prostate cancer. Throughout the genome, ERG-binding sites were the ones with differences in chromatin loop interactions between the control (GFP) and ERG over-expressing cells.
In both cell lines, the most highly expressed genes tended to group into chromatin clusters the authors describe as ‘transcriptional hubs’. Comparing the functions of genes in these high activity regions in the two, they found that the chromatin clusters in the ERG-expressing cell line had more genes associated with cell motility, invasion and de-differentiation of prostate-specific cells. Not all these changes lasted consistently through all ERG-overexpressing cells, however. Some of these chromatin interactions depended on what phase of cell division cells were going through- dividing cells in the G2/M phases had different interactions than cells in the G1 growth phase. When the researchers repeated these experiments in DU-145, a different cell line, only some of the chromatin interactions were the same as those in RWPE-1.
Organizing chromatin loops based on activity levels into highly active (or repressed) clusters is an efficient way for cells to modify the functions of groups of genes. Tumors with ERG gene fusion events behave differently from other tumors, enough to be considered a distinct sub-type of prostate cancer. This study shows that the gene expression signatures in cancers with such gene fusions are also associated with large-scale chromatin restructuring. As the authors also point out, the link between chromatin structure and gene expression is not necessarily a cause and effect relationship. However, a related study in Cell last week adds some perspective on this aspect. In the Cell paper, authors Deng et al. used a zinc-finger binding protein to force distant regions of chromatin into looping together. They found that these forced re-arrangements of chromatin could increase or decrease expression of genes within the restructured loops.
Designing molecules that loop or un-loop specific regions of DNA could be a quick way to increase or decrease the activity of clusters of tumor-associated genes. Many recent studies sequencing tumor genomes highlight how each tumor is unique. In some cases, even cells within a single tumor may have distinctly different genomic changes. The links between these sequence-level changes and larger scale changes in chromosome structure are still murky. By studying the 3D maps of cancer genomes described in these papers, scientists may be able to find common chromosome-scale patterns that could correlate to sequence-level changes like the ERG gene fusions.
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