One aspect of translocations and their association with malignancy that has largely been ignored is the impact of altered nuclear organization on the regulation of surrounding genes. Indeed, changes in the activation status of oncogenes or tumor suppressors not directly involved in the translocation event could occur as a result of changes in nuclear organization and these could synergize with the initiating lesion to promote or accelerate oncogenesis. Indeed in many instances, signature translocations associated with malignancies do not on their own lead to cellular transformation so we need a better understanding of the pathways that drive oncogenesis and disease progression. Since chromosomes are organized in a nonrandom lineage and developmental stage specific fashion that impacts on gene regulation, we hypothesize that translocation-mediated alterations in spatial organization will have an effect on the regulation of numerous genes, changing their transcriptional output. This hypothesis is based on published data from the Skok lab demonstrating that short and long-range interactions can have a significant effect on gene regulation in cis and in trans 1, 2. Furthermore, we now have preliminary data showing that gene targeting of a single regulatory element can significantly disrupt the control and expression of multiple genes in a manner that is linked to changes in their interactomes. Alterations in nuclear organization linked to widespread changes in gene regulation have not been looked at in the context of any chromosomal translocation event. Given the multitude of signature translocations that are associated with particular cancers this warrants in-depth investigation. Since genes on the same chromosome interact with each other much more frequently than genes on different chromosomes, translocations that join two parts of different chromosomes together will disrupt the normal cis interaction profiles of the partners involved, and this in tur will impact trans interactions. Thus, the interactomes of co-regulated genes will be altered in a manner that will likely change the nuclear distribution and concentration of transcription factors and the regulation of multiple genes. To address this question we aim to analyze two translocations that are implicated in acute lymphoblastic leukemia (ALL): IGH-CRLF2, which is associated with B-ALL and TCRB-NOTCH1, a translocation associated with T-ALL. The focus here will be on the interactomes of the partner genes themselves: we will identify the translocation- mediated changes in each locus's interaction network and couple this with analysis of changes in expression, regulation and transcription factor binding of the genes involved. Our integrative approach will provide new insight into the impact of translocations from a perspective that has not previously been explored. This will be the first step in understanding the scale of the impact of a translocation on the 3D nucleome and further, in addressing the question of whether the changes that we observe can be explained by the current models of gene regulation.
Numerous malignancies have been associated with signature translocations in which an oncogene becomes deregulated through joining with another gene that exerts control over its expression. However, in many instances the translocation alone is insufficient for transformation, and additional cooperating mutations and deletions are thought to contribute, but it is unclear how these arise. To address this question we aim to examine how alterations in the organization of the genome that result from an abnormal chromosomal rearrangement event, impact on the regulation of surrounding loci in a manner that could contribute to oncogenesis.
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|Modrek, Aram S; Golub, Danielle; Khan, Themasap et al. (2017) Low-Grade Astrocytoma Mutations in IDH1, P53, and ATRX Cooperate to Block Differentiation of Human Neural Stem Cells via Repression of SOX2. Cell Rep 21:1267-1280|
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