A method which enables the investigation of the buried interfaces without altering the properties of the polymer films is used to study vertical phase separation of spin‐coated poly(3‐hexylthiophene) (P3HT):fullerene derivative blends. X‐ray photoelectron spectroscopy (XPS) and atomic force microscopy (AFM) analysis reveals the P3HT enrichment at the free (air) surfaces and abundance of fullerene derivatives at the organic/substrate interfaces. The vertical phase separation is attributed to the surface energy difference of the components and their interactions with the substrates. This inhomogeneous distribution of the donor and acceptor components significantly affects photovoltaic device performance and makes the inverted device structure a promising choice.

Oncogene-induced senescence is a potent barrier to tumorigenesis that limits cellular expansion following certain oncogenic events. Senescent cells display a repressive chromatin configuration thought to stably silence proliferation-promoting genes, while simultaneously activating an unusual form of immune surveillance involving a secretory program referred to as the senescence-associated secretory phenotype (SASP). Here we demonstrate that senescence also involves a global remodeling of the enhancer landscape with recruitment of the chromatin reader BRD4 to newly activated super-enhancers adjacent to key SASP genes. Transcriptional profiling and functional studies indicate that BRD4 is required for the SASP and downstream paracrine signaling. Consequently, BRD4 inhibition disrupts immune cell mediated targeting and elimination of premalignant senescent cells in vitro and in vivo. Our results identify a critical role for BRD4-bound super-enhancers in senescence immune surveillance and in the proper execution of a tumor-suppressive program.

Summary Metastatic prostate cancer is characterized by recurrent genomic copy number alterations that are presumed to contribute to resistance to hormone therapy. We identified CHD1 loss as a cause of antiandrogen resistance in an in vivo small hairpin RNA (shRNA) screen of 730 genes deleted in prostate cancer. ATAC-seq and RNA-seq analyses showed that CHD1 loss resulted in global changes in open and closed chromatin with associated transcriptomic changes. Integrative analysis of this data, together with CRISPR-based functional screening, identified four transcription factors (NR3C1, POU3F2, NR2F1, and TBX2) that contribute to antiandrogen resistance, with associated activation of non-luminal lineage programs. Thus, CHD1 loss results in chromatin dysregulation, thereby establishing a state of transcriptional plasticity that enables the emergence of antiandrogen resistance through heterogeneous mechanisms.

Complete surgical resection is the first-line treatment for most liver malignancies. This goal would be facilitated by an intraoperative imaging method that enables more precise visualization of tumor margins, and detection of otherwise invisible microscopic lesions. To this end, we synthesized silica-encapsulated surface-enhanced Raman scattering (SERS) nanoparticles (NPs) that act as a molecular imaging agent for liver malignancies. We hypothesized that, after intravenous administration, SERS NPs would avidly home to healthy liver tissue, but not to intrahepatic malignancies. We tested these SERS NPs in genetically engineered mouse models of hepatocellular carcinoma and histiocytic sarcoma. After intravenous injection, liver tumors in both models were readily identifiable with Raman imaging. In addition, Raman imaging using SERS NPs enabled detection of microscopic lesions in liver and spleen. We compared the performance of SERS NPs to fluorescence imaging using Indocyanine Green (ICG). We found that SERS NPs delineate tumors more accurately and are less susceptible to photobleaching. Given the known advantages of SERS imaging, namely high sensitivity and specific spectroscopic detection, these findings hold promise for improved resection of liver cancer.

In the originally published version of this article, there is a duplicated western blot panel in Figure 5D. This figure shows the co-immunoprecipitation of BRG1 and members of the polycomb repressive complex 1.1 together with HA-SS18-SSX1. The image for the BRG1 western blot was inadvertently inserted instead of the BCOR western blot. The error occurred when re-introducing original western blot images to enhance image quality for publication. The correct Figure 5D, as originally submitted to Cancer Cell, is now shown here and in the online version of the paper. The authors apologize for any confusion this error may have caused.

No abstract

Transcription-generated DNA supercoiling plays a decisive role in a promoter relay mechanism for the coordinated expression of genes in the Salmonella typhimurium ilvIH-leuO-leuABCD gene cluster. A similar mechanism also operates to control expression of the genes in the Escherichia coli ilvIH-leuO-leuABCD gene cluster. However, the mechanism underlying the DNA supercoiling effect remained elusive. A bacterial gene silencer AT8 was found to be important for the repression state of the leuO gene as part of the promoter relay mechanism. In this communication, we demonstrated that the gene silencer AT8 is a nucleation site for recruiting histone-like nucleoid structuring protein to form a cis-spreading nucleoprotein filament that is responsible for silencing of the leuO gene. With a DNA geometric similarity rather than a DNA sequence specificity, the E. coli gene silencer EAT6 was capable of replacing the histone-like nucleoid structuring protein nucleation function of the S. typhimurium gene silencer AT8 for the leuO gene silencing. The interchangeability between DNA geometrical elements for supporting the silencing activity in the region is consistent with a previous finding that a neighboring transcription activity determines the outcome of the gene silencing activity. The geometric requirement, which was revealed for this silencing activity, explains the decisive role of transcription-generated DNA supercoiling found in the promoter relay mechanism.DNA supercoiling has been known to play important roles in transcriptional regulation (1-7). By using a bacterial transcription regulation model system, we have demonstrated that transcription-generated DNA supercoiling is a crucial driven force that triggers the sequential activation of genes in the Salmonella typhimurium ilvIH-leuO-leuABCD gene cluster (8 -12). This rather complex sequential gene activation process was named the promoter relay mechanism (11, 12). The exact molecular detail that underlies the effect of transcription-generated DNA supercoiling on the sequential activation of genes at this locus remains unclear. The direct DNA supercoiling effect on activating promoters of genes in this region has been ruled out. Instead, the effect appears to mediate through cis-elements within the locus control regions (LCRs 1 illustrated in Fig. 1) located between genes in the ilvIH-leuO-leuABCD gene cluster (8).Although not ruling out the possible involvement of other cis-acting elements in the transcription regulation, we have identified two cis-elements in the LCR-I that are important for the promoter relay mechanism as follows: a bacterial gene silencer, termed AT8; and a LeuO protein-binding site, termed AT7 (13, 14). The bacterial gene silencer AT8-mediated transcriptional silencing is integral to the gene expression regulation and is responsible for the repressed state of the leuO gene. LeuO protein-mediated derepression, which relieves the repression of leuO gene, is also a crucial part of the promoter relay mechanism. Transcription-generated DNA supercoili...

Synovial sarcoma is an aggressive cancer invariably associated with a chromosomal translocation involving genes encoding the SWI-SNF complex component SS18 and an SSX (SSX1 or SSX2) transcriptional repressor. Using functional genomics, we identify KDM2B, a histone demethylase and component of a non-canonical polycomb repressive complex 1 (PRC1.1), as selectively required for sustaining synovial sarcoma cell transformation. SS18-SSX1 physically interacts with PRC1.1 and co-associates with SWI/SNF and KDM2B complexes on unmethylated CpG islands. Via KDM2B, SS18-SSX1 binds and aberrantly activates expression of developmentally regulated genes otherwise targets of polycomb-mediated repression, which is restored upon KDM2B depletion, leading to irreversible mesenchymal differentiation. Thus, SS18-SSX1 deregulates developmental programs to drive transformation by hijacking a transcriptional repressive complex to aberrantly activate gene expression.