ABSTRACT
3D chromatin organization plays an important role in transcription regulation and gene expression. The 3D genome is highly maintained by several architectural proteins, such as CTCF, Yin Yang 1, and cohesin complex. This structural organization brings regulatory DNA elements in close proximity to their target promoters. In this review, we discuss the 3D chromatin organization of super-enhancers and their relationship to phase-separated condensates. Super-enhancers are large clusters of DNA elements. They can physically contact with their target promoters by chromatin looping during transcription. Multiple transcription factors can bind to enhancer and promoter sequences and recruit a complex array of transcriptional co-activators and RNA polymerase II to effect transcriptional activation. Phase-separated condensates of transcription factors and transcriptional co-activators have been implicated in assembling the transcription machinery at particular enhancers. Cancer cells can hijack super-enhancers to drive oncogenic transcription to promote cell survival and proliferation. These dysregulated transcriptional programs can cause cancer cells to become highly dependent on transcriptional regulators, such as Mediator and BRD4. Moreover, the expression of oncogenes that are driven by super-enhancers is sensitive to transcriptional perturbation and often occurs in phase-separated condensates, supporting therapeutic rationales of targeting SE components, 3D genome organization, or dysregulated condensates in cancer.
ABSTRACT
Low brain accumulation of anticancer drugs due to efflux transporters may limit chemotherapeutic efficacy, necessitating a better understanding of the underlying mechanisms. P-glycoprotein (Abcb1a/1b) and breast cancer resistance protein (Abcg2) combination knockout mice often display disproportionately increased brain accumulation of shared drug substrates compared with single transporter knockout mice. Recently developed pharmacokinetic models could explain this phenomenon. To experimentally test these models and their wider relevance for tyrosine kinase inhibitors and other drugs, we selected dasatinib, sorafenib, and sunitinib because of their divergent oral availability and brain accumulation profiles: the brain accumulation of dasatinib is mainly restricted by Abcb1, that of sorafenib mainly by Abcg2, and that of sunitinib equally by Abcb1 and Abcg2. We analyzed the effect of halving the efflux activity of these transporters at the blood-brain barrier by generating heterozygous Abcb1a/1b;Abcg2 knockout mice and testing the plasma and brain levels of the drugs after oral administration at 10 mg/kg. Real-time reverse transcription-polymerase chain reaction analysis confirmed the â¼2-fold decreased expression of both transporters in brain. Interestingly, whereas complete knockout of the transporters caused 24- to 36-fold increases in brain accumulation of the drugs, the heterozygous mice only displayed 1.6- to 1.9-fold increases of brain accumulation relative to wild-type mice. These results are well in line with the predictions of the pharmacokinetic models and provide strong support for their validity for a wider range of drugs. Moreover, retrospective analysis of fetal accumulation of drugs across the placenta in Abcb1a/1b heterozygous knockout pups suggests that these models equally apply to the maternal-fetal barrier.