Question

Super enhancers have been shown to regulate the expression of oncogenes like Myc. These super enhancers can be targeted by small molecule inhibitors to histone readers like BRD4. Inhibiting histone readers like BRD4 has been leveraged as a therapeutic strategy to repress oncogene expression (i.e. Myc) in specific tumor types. Can you further explain the rationale behind this approach by addressing the following questions? A.) Does BRD4 occupy super enhancers to a different extent than regular enhancers? If so, why does BRD4 bind to super enhancers differently? B.) Would BRD4 inhibition affect normal enhancers in the patient’s body to the same extent as the active super enhancers in the patient’s tumor? If yes or no why? C.) Would BRD4 inhibition in tumors of different origin (lymphoma vs neuroblastoma) affect the expression of the same oncogenes? If yes or no why?

Answer 1

ANSWER A :-

1. Enhancer is basically a sequence which is regulatory in function. BRD4 also called as 'bromodomain' acts as a transcriptional activator which tends to binds to super enhancers more effectively than that of the enhancers.
2. BRD4 acts as a histone reader which tends to identify the Acetylated lysine residues in histone as a part of histone modification. BRD4 binding to chromatin having enhancer region would not show much binding strength as compared to that of a superenhancer which has Multiple enhancer elements grouped with Multiple transcription factors that eases binding of BRD-4.
3. This is the reason for difference in binding of BRD4 with respect to enhancer and super enhancer elements.

ANSWER B :-

1. ​​​​​​As already stated above, BRD4 basically tends to be associated with super enhancer elements.
2. JQ1 is basically a potent inhibitor which marks decreasing the binding potential between the super enhancer elements and the BRD4 thereby inhibiting transcriptional activation.
3. The specificity of binding is only restricted to the domain BR-I and BR-II of BRD4 and this marks specific inhibition. Enhancer elements do not show such a mediated activity and hence the extent of effect in carrying out inhibition would not be that prominent. Tumor cells shows enhanced expression of many transcriptional factors and activators and at the same time unregulated expression of target oncogenes. This is thus restricted by inhibitors which are directed specifically towards the BRD4 domain which are associated with enhancement in oncogenic expression.

ANSWER C :-

1. Different tumors are associated with differential expression of BRD4 and other related bromodomains. Although, JQ1 is used as an effective inhibitor for various bromodomains, the functional dose varies depends upon the severity of tumor as well as the expression levels of the BRD4.
2. The point behind covering this information is that there is a factorial expression of several oncogenes as they are associated with higher expression and activation of gene transcription event thereby leading to a profound and differential effect in different tissues associated with cancer.

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