Person:

Day, Daniel

We describe computational methods for analysis of repetitive elements from short-read sequencing data, and apply them to study histone modifications associated with the repetitive elements in human and mouse cells. Our results demonstrate that while accurate enrichment estimates can be obtained for individual repeat types and small sets of repeat instances, there are distinct combinatorial patterns of chromatin marks associated with major annotated repeat families, including H3K27me3/H3K9me3 differences among the endogenous retroviral element classes.

The CCCTC-binding factor (CTCF), which anchors DNA loops that organize the genome into structural domains, plays a central role in gene control by facilitating or constraining interactions between genes and their regulatory elements. In cancer cells the disruption of CTCF binding at specific loci through somatic mutation or DNA hypermethylation5 results in the loss of loop anchors and consequent activation of oncogenes. By contrast, the germ cell-specific paralog of CTCF, BORIS (Brother of the Regulator of Imprinted Sites), is overexpressed in multiple cancers, but its contributions to the malignant phenotype remain unclear. Here we show that aberrant upregulation of BORIS promotes novel chromatin interactions in ALK-mutated, MYCN-amplified neuroblastoma cells rendered resistant to ALK inhibition. These cells are reprogrammed to a distinct phenotypic state during the acquisition of resistance, a process defined by the initial loss of MYCN expression followed by subsequent overexpression of BORIS and a concomitant switch in cellular dependence from MYCN to BORIS. The resultant BORIS-regulated alterations in chromatin looping lead to the formation of new super-enhancers that drive the ectopic expression of a subset of proneural transcription factors that ultimately define the resistance phenotype. These results identify a previously unrecognized role of BORIS – to engender regulatory chromatin interactions that support specific cancer phenotypes.