Alveolar rhabdomyosarcoma is a life-threatening myogenic cancer of children and adolescent young adults, driven primarily by the chimeric transcription factor PAX3-FOXO1. The mechanisms by which PAX3-FOXO1 dysregulates chromatin are unknown. We fi nd PAX3-FOXO1 reprograms the cis -regulatory landscape by inducing de novo super enhancers. PAX3-FOXO1 uses super enhancers to set up autoregulatory loops in collaboration with the master transcription factors MYOG, MYOD, and MYCN. This myogenic super enhancer circuitry is consistent across cell lines and primary tumors. Cells harboring the fusion gene are selectively sensitive to small-molecule inhibition of protein targets induced by, or bound to, PAX3-FOXO1-occupied super enhancers. Furthermore, PAX3-FOXO1 recruits and requires the BET bromodomain protein BRD4 to function at super enhancers, resulting in a complete dependence on BRD4 and a signifi cant susceptibility to BRD inhibition. These results yield insights into the epigenetic functions of PAX3-FOXO1 and reveal a specifi c vulnerability that can be exploited for precision therapy.SIGNIFICANCE: PAX3-FOXO1 drives pediatric fusion-positive rhabdomyosarcoma, and its chromatinlevel functions are critical to understanding its oncogenic activity. We fi nd that PAX3-FOXO1 establishes a myoblastic super enhancer landscape and creates a profound subtype-unique dependence on BET bromodomains, the inhibition of which ablates PAX3-FOXO1 function, providing a mechanistic rationale for exploring BET inhibitors for patients bearing PAX-fusion rhabdomyosarcoma. Cancer Discov; 7(8);

SUMMARY We report a mechanism through which the transcription machinery directly controls topoisomerase 1 (TOP1) activity to adjust DNA topology throughout the transcription cycle. By comparing TOP1 occupancy using ChIP-Seq, versus TOP1 activity using TOP1-Seq, a method reported here to map catalytically engaged TOP1, TOP1 bound at promoters was discovered to become fully active only after pause-release. This transition coupled the phosphorylation of the carboxyl-terminal-domain (CTD) of RNA polymerase II (RNAPII) with stimulation of TOP1 above its basal rate, enhancing its processivity. TOP1 stimulation is strongly dependent on the kinase activity of BRD4, a protein that phosphorylates Ser2-CTD and regulates RNAPII pause-release. Thus the coordinated action of BRD4 and TOP1 overcame the torsional stress opposing transcription as RNAPII commenced elongation, but preserved negative supercoiling that assists promoter melting at start sites. This nexus between transcription and DNA topology promises to elicit new strategies to intercept pathological gene expression.

This review especially focuses on the advances in heterogeneous dye-sensitized semiconductors for H2 production during the past 30 years.

High-quality multicolor 2D and 3D meta-holography is realized based on broadband plasmonic modulation.

Two kinds of graphitic carbon nitride (g-C 3 N 4 ) were synthesized through a pyrolysis process of urea or melamine. It is found that the obtained g-C 3 N 4 , as photocatalysts, can reduce CO 2 to organic fuels under visible light, and exhibit different photoactivity and selectivity on the formation of CH 3 OH and C 2 H 5 OH. The product derived from the urea (denoted as u-g-C 3 N 4 ) shows a mesoporous flake-like structure with a larger surface area and higher photoactivity for the CO 2 reduction than the non-porous flaky product obtained from melamine (denoted as m-g-C 3 N 4 ). Moreover, using u-g-C 3 N 4 as a photocatalyst can result in the formation of a mixture containing CH 3 OH and C 2 H 5 OH, while m-g-C 3 N 4 only leads to the selective formation of C 2 H 5 OH. The present interesting findings could shed light on the design of efficient, eco-friendly and convenient photocatalysts and the tuning of their photoreactivity in the field of sustainable light-to-energy conversion.