Targetable BET proteins- and E2F1-dependent transcriptional program maintains the malignancy of glioblastoma.

Competitive BET bromodomain inhibitors (BBIs) targeting BET proteins (BRD2, BRD3, BRD4, and BRDT) show promising preclinical activities against brain cancers. However, the BET protein-dependent glioblastoma (GBM)-promoting transcriptional network remains elusive. Here, with mechanistic exploration of a next-generation chemical degrader of BET proteins (dBET6), we reveal a profound and consistent impact of BET proteins on E2F1- dependent transcriptional program in both differentiated GBM cells and brain tumor-initiating cells. dBET6 treatment drastically reduces BET protein genomic occupancy, RNA-Pol2 activity, and permissive chromatin marks. Subsequently, dBET6 represses the proliferation, self-renewal, and tumorigenic ability of GBM cells. Moreover, dBET6-induced degradation of BET proteins exerts superior antiproliferation effects compared to conventional BBIs and overcomes both intrinsic and acquired resistance to BBIs in GBM cells. Our study reveals crucial functions of BET proteins and provides the rationale and therapeutic merits of targeted degradation of BET proteins in GBM.

In Situ Spectroscopic Elucidation of the Electrochemical Potential Drop at Polyelectrolytes/Au Interfaces.

Polyelectrolytes have been widely applied in electrochemical devices. Understanding the polyelectrolyte/electrode interfaces is pivotal for polyelectrolyte-based applications. Here, we measured the electrochemical potential drop and the local activity of the mobile ion of H+ or OH- at the polyelectrolytes/Au interfaces by in situ electrochemical surface-enhanced Raman spectroscopy and voltammetry in three-electrode cells. We found that the potential dependences of the electrochemical potential drop in polyelectrolytes were smaller than that in conventional electrolyte solutions. The interfacial activity of H+ or OH- was much lower than that of bulk polyelectrolytes. The potential-dependent molecular dynamics simulations showed that the mobility of ionomers of polyelectrolytes in an electrostatic field was limited by a polymer matrix. These results suggested a characteristically thicker compact layer in the electrical double layer of a polyelectrolyte/electrode interface due to the accumulation of mobile H+ or OH- with a thicker hydration layer and immobile ionomers.

[Analysis of horizontal transfer gene of Bombyx mori NPV].

For research on genetic characters and evolutionary origin of the genome of baculoviruses, a comprehensive homology search and phylogenetic analysis of the complete genomes of Bombyx mori NPV and Bombyx mori were used. Three horizontally transferred genes (inhibitor of apoptosis, chitinase, and UDP-glucosyltransferase) were identified, and there was evidence that all of these genes were derived from the insect host. The results of analysis showed lots of differences between the features of horizontal transferred genes and the ones of whole genomic genes, such as nucleotide composition, codon usagebias and selection pressure. These results reconfirmed that the horizontally transferred genes are exogenous. The analysis of gene function suggested that horizontally transferred genes acquired from an ancestral host insect can increase the efficiency of baculoviruses transmission.

Topography of transcriptionally active chromatin in glioblastoma.

Molecular profiling of the most aggressive brain tumor glioblastoma (GBM) on the basis of gene expression, DNA methylation, and genomic variations advances both cancer research and clinical diagnosis. The enhancer architectures and regulatory circuitries governing tumor-intrinsic transcriptional diversity and subtype identity are still elusive. Here, by mapping H3K27ac deposition, we analyze the active regulatory landscapes across 95 GBM biopsies, 12 normal brain tissues, and 38 cell line counterparts. Analyses of differentially regulated enhancers and super-enhancers uncovered previously unrecognized layers of intertumor heterogeneity. Integrative analysis of variant enhancer loci and transcriptome identified topographies of transcriptional enhancers and core regulatory circuitries in four molecular subtypes of primary tumors: AC1-mesenchymal, AC1-classical, AC2-proneural, and AC3-proneural. Moreover, this study reveals core oncogenic dependency on super-enhancer-driven transcriptional factors, long noncoding RNAs, and druggable targets in GBM. Through profiling of transcriptional enhancers, we provide clinically relevant insights into molecular classification, pathogenesis, and therapeutic intervention of GBM.

Bromodomain and extraterminal proteins foster the core transcriptional regulatory programs and confer vulnerability in liposarcoma.

Liposarcomas (LPSs) are a group of malignant mesenchymal tumors showing adipocytic differentiation. Here, to gain insight into the enhancer dysregulation and transcriptional addiction in this disease, we chart super-enhancer structures in both LPS tissues and cell lines. We identify a bromodomain and extraterminal (BET) protein-cooperated FUS-DDIT3 function in myxoid LPS and a BET protein-dependent core transcriptional regulatory circuitry consisting of FOSL2, MYC, and RUNX1 in de-differentiated LPS. Additionally, SNAI2 is identified as a crucial downstream target that enforces both proliferative and metastatic potentials to de-differentiated LPS cells. Genetic depletion of BET genes, core transcriptional factors, or SNAI2 mitigates consistently LPS malignancy. We also reveal a compelling susceptibility of LPS cells to BET protein degrader ARV-825. BET protein depletion confers additional advantages to circumvent acquired resistance to Trabectedin, a chemotherapy drug for LPS. Moreover, this study provides a framework for discovering and targeting of core oncogenic transcriptional programs in human cancers.

Co-activation of super-enhancer-driven CCAT1 by TP63 and SOX2 promotes squamous cancer progression.

Squamous cell carcinomas (SCCs) are aggressive malignancies. Previous report demonstrated that master transcription factors (TFs) TP63 and SOX2 exhibited overlapping genomic occupancy in SCCs. However, functional consequence of their frequent co-localization at super-enhancers remains incompletely understood. Here, epigenomic profilings of different types of SCCs reveal that TP63 and SOX2 cooperatively and lineage-specifically regulate long non-coding RNA (lncRNA) CCAT1 expression, through activation of its super-enhancers and promoter. Silencing of CCAT1 substantially reduces cellular growth both in vitro and in vivo, phenotyping the effect of inhibiting either TP63 or SOX2. ChIRP analysis shows that CCAT1 forms a complex with TP63 and SOX2, which regulates EGFR expression by binding to the super-enhancers of EGFR, thereby activating both MEK/ERK1/2 and PI3K/AKT signaling pathways. These results together identify a SCC-specific DNA/RNA/protein complex which activates TP63/SOX2-CCAT1-EGFR cascade and promotes SCC tumorigenesis, advancing our understanding of transcription dysregulation in cancer biology mediated by master TFs and super-enhancers.

In silico analysis of plant and animal transposable elements.

Transposable Elements (TEs) play important roles in the evolution of eukaryotic organisms. TEs widely distribute depending on their properties present in the genome. This study elucidated the molecular characteristics of TEs in land plants and animals using bioinformatics and in silico mutational approach. We discovered that the GC-rich class I TEs is the predominant class of TEs in animal, but the AT-rich class II TEs is prevalent in plants. The GC-rich class I TEs appears to be evolved within the animals. On contrary, the preserved in AT-rich in class II TEs is believed to be contributed in host defence systems.

Molecular analysis of early rice stamen development using organ-specific gene expression profiling.

Elucidating the regulatory mechanisms of plant organ formation is an important component of plant developmental biology and will be useful for crop improvement applications. Plant organ formation, or organogenesis, occurs when a group of primordial cells differentiates into an organ, through a well-orchestrated series of events, with a given shape, structure and function. Research over the past two decades has elucidated the molecular mechanisms of organ identity and dorsalventral axis determinations. However, little is known about the molecular mechanisms underlying the successive processes. To develop an effective approach for studying organ formation at the molecular level, we generated organ-specific gene expression profiles (GEPs) reflecting early development in rice stamen. In this study, we demonstrated that the GEPs are highly correlated with early stamen development, suggesting that this analysis is useful for dissecting stamen development regulation. Based on the molecular and morphological correlation, we found that over 26 genes, that were preferentially up-regulated during early stamen development, may participate in stamen development regulation. In addition, we found that differentially expressed genes during early stamen development are clustered into two clades, suggesting that stamen development may comprise of two distinct phases of pattern formation and cellular differentiation. Moreover, the organ-specific quantitative changes in gene expression levels may play a critical role for regulating plant organ formation.