A new study clarifies how BRD4 (a protein that scientists have studied for many years) directs the spatial organization of DNA in the cell nucleus (a key function of stem cells to differentiate into muscle cells), which promotes the understanding of certain cancers and complex congenital diseases. Since the way DNA is folded is essential for gene regulation, this research not only has implications for a series of genetic diseases including heart defects, cleft palate, microcephaly, and intellectual disability, but will also better guide BRD4 targeting drug development, some of which are undergoing clinical trials, as promising interventions for the treatment of cancer and heart disease. The results of the study are published in Nature Genetics.
“Inhibition of BRD4 and a class of proteins to which it belongs has always been regarded as a very attractive area of cancer research.” said Rajan Jain, MD, assistant professor of medicine and cell and developmental biology at the Perelman School of Medicine at the University of Pennsylvania and senior author. “Our data underscore the importance of trying to use inhibitors that affect specific functions of BRD4. The negative results of clinical trials that inhibit BRD4 may be because too many functions are inhibited, so by understanding all the different functions, we can finally design drugs that affect one function of BRD4 but not another.”
BRD4 is called the “Swiss Army Knife” of the cell because it can regulate many aspects of gene activation, usually as an active regulatory process that allows certain genes to be activated. BRD4 regulates genes including those related to cell growth and division. If these genes are turned on abnormally, they may cause certain cancers, including several leukemias. Given the growth-promoting function of BRD4, inhibiting BRD4 seems to be a promising strategy to combat these cancers. However, the results of clinical studies of some BRD4 inhibitors indicate that inhibition of BRD4 may be a complicated matter.
Jain’s team showed that BRD4′s function in genome folding is different from its function of keeping genes on. However, in principle, drugs that bind BRD4 in a specific way may inhibit one or both of these functions, which means that it is necessary to consider drugs that target one or the other of BRD4 and related proteins.
Jain said: “Inhibitors that block BRD4 may also disrupt the proper folding of DNA in certain cells.” “So I think our work reveals another layer of complexity in this protein, when researchers tried to use brd4 to affect inhibition. This should be relevant when the agent interprets their results.”
Mutations in BRD4 are also related to cohesive diseases, which are a group of congenital syndromes, including Cornelia De Lange syndrome and Roberts syndrome, which usually severely damage and shorten the lives of patients. Cohesive protein is a multi-protein molecular machine that helps DNA folding and curling in cells. Cohesive protein disease will occur when cohesive protein dysfunction. So far, how BRD4 participates in the work of cohesion is largely unknown. In this study, the researchers found that the absence of neural crest BRD4 causes embryos to have characteristics similar to those of human homologous diseases. The neural crest is a highly specialized subset of cells that become tissues in the face, heart, brain, and other organs.
Jain and his colleagues hypothesized that BRD4 tells new cells how to fold their DNA, thereby turning on the correct genes for that cell type, and hope to prove or disprove this hypothesis in upcoming studies.