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Somatic stem cells contribute to normal tissue homeostasis, and their epigenomic features play an important role in regulating tissue identities or developing disease states. Enhancers are one of the key players controlling chromatin context-specific gene expression in a spatial and temporal manner while maintaining tissue homeostasis, and their dysregulation leads to tumorigenesis. Here, epigenomic and transcriptomic analyses reveal that forkhead box protein D2 (FOXD2) is a hub for the gene regulatory network exclusive to large intestinal stem cells, and its overexpression plays a significant role in colon cancer regression. FOXD2 is positioned at the closed chromatin and facilitates mixed-lineage leukemia protein-4 (MLL4/KMT2D) binding to deposit H3K4 monomethylation. De novo FOXD2-mediated chromatin interactions rewire the regulation of p53-responsive genes and induction of apoptosis. Taken together, our findings illustrate the novel mechanistic details of FOXD2 in suppressing colorectal cancer growth and suggest its function as a chromatin-tuning factor and a potential therapeutic target for colorectal cancer.

Current organoid models are limited by their inability to mimic mature organ architecture and associated tissue microenvironments1,2. Here we create multilayer bladder ‘assembloids’ by reconstituting tissue stem cells with stromal components to represent an organized architecture with an epithelium surrounding stroma and an outer muscle layer. These assembloids exhibit characteristics of mature adult bladders in cell composition and gene expression at the single-cell transcriptome level, and recapitulate in vivo tissue dynamics of regenerative responses to injury. We also develop malignant counterpart tumour assembloids to recapitulate the in vivo pathophysiological features of urothelial carcinoma. Using the genetically manipulated tumour-assembloid platform, we identify tumoural FOXA1, induced by stromal bone morphogenetic protein (BMP), as a master pioneer factor that drives enhancer reprogramming for the determination of tumour phenotype, suggesting the importance of the FOXA1–BMP–hedgehog signalling feedback axis between tumour and stroma in the control of tumour plasticity. Multilayer 3D reconstitution of bladder stem cells with stromal cells enables recapitulation of the architecture and molecular functions of bladder tissue.

Spontaneous activation of macrophages in response to inflammation is a key part of innate immunity and host defense. Macrophages represent a heterogeneous population of cells with different phenotypic profiles performing distinct functions in host defense. Although a spectrum of macrophage activation stages exists in an inflamed region, the effect of local physical conditions on the heterotypic activation of macrophages is unknown. Here, we introduce an in vivo fluid-matrix interface analogous culture platform, an asymmetric microenvironment, facilitating the formation of macrophage aggregates (MAs). Macrophages were self-assembled to form MAs of ∼100 μm diameter at the collagen matrix-medium interface upon phorbol-12-myristate-13-acetate treatment. The macrophages within the half-embedded MAs into the matrix were heterogeneously activated, resulting in inhomogeneous cell-cell and cell-matrix interactions within the aggregates. Our demonstration may aid in a better understanding of the acquisition of macrophage heterogeneity in response to tissue-specific microenvironments.

We report flexible oxide semiconductor-based electronics transferred on polydimethylsiloxane (PDMS) elastomer substrate in the form of stiff stripes for stretchable displays. Stiff stripes with optimized geometries are placed between PDMS substrate and oxide electronics to provide strong adhesion and mechanical protection. Amorphous indium–gallium–zinc oxide (a-IGZO) thin-film transistors (TFTs) and gate driver circuits on polyimide substrate are cut into identical stripe shape and transferred onto the stiff region. The turn-on voltage ( ${V}_{ \mathrm{\scriptscriptstyle ON}}$ ) and mobility of the fabricated a-IGZO TFTs vary within ±0.4 V and 7.4%, respectively, after 50% stretching and relaxation for 1000 cycles. The circuits on the stiff-stripe/elastomer substrate can be repeatedly stretched to 50% without mechanical and electrical degradations. The results can be used for practical stretchable displays with high resolution over a large area.

Despite the immense research on quantum dot light emitting diodes (QLEDs), there are still some challenges for QLEDs such as improvements of efficiency roll-off at high luminance and poor lifetime. Here, we demonstrated a remarkable improvement of the efficiency roll-off and operational lifetime in inverted, red quantum dot light emitting diodes (R-QLEDs) by incorporating rubidium carbonate (Rb2CO3) into the Mg doped ZnO (MZO) electron transporting layer (ETL). The optimum Rb2CO3 doping concentration and thickness for the ETL are found to be 4% and 90 nm, respectively. The R-QLED with the 90 nm Rb2CO3 doped MZO ETL with 4% doping shows a long operational lifetime (T90) of 14 672 h at the initial luminance of 100 cd m−2, a maximum luminance of 129 100 cd m−2 and a high current efficiency (CE) of 13.6 cd A−1 at a high luminance of 60 000 cd m−2. These improvements appear to be due to the fact that Rb2CO3 acts as a strong n-type dopant and enhances the thermal stability of MZO according to various thin-film analyses.

Inorganic cesium lead bromide quantum dots (CsPbBr3 QDs) are usually synthesized via a high-temperature process (hot injection, HI). This process is similar to that used for the synthesis of other semiconductor QDs (i.e., CdSe@ZnS), which limits their potential cost advantage. CsPbBr3 QDs can also be synthesized at room temperature (RT) in a low cost and easily scalable process, which, thus, is one of the greatest advantages of the CsPbBr3 QDs. However, light-emitting diodes (LEDs) fabricated using RT-QDs exhibit poor performance compared to those of HI-QDs. In fact, QDs are surrounded by insulating ligands to maintain their colloidal stability but these ligands need to be removed to obtain high-performance LEDs. Here, we show that ligand removal techniques used for HI-QDs are not sufficient in the case of RT-QDs. Additional ligand engineering and annealing steps are necessary to remove the excess of ligands from RT-QD films while preventing the coalescence of the QDs. The eventual surface defects induced...

Retinoic acid-related orphan receptor γ (RORγ) maintains the circadian rhythms of its downstream genes. However, the mechanism behind the transcriptional activation of RORγ itself remains unclear. Here, we demonstrate that transcription of RORγ is activated by heterogeneous nuclear ribonucleoprotein K (hnRNP K) via the poly(C) motif within its proximal promoter. Interestingly, we confirmed the binding of endogenous hnRNP K within RORγ1 and RORγ2 promoter along with the recruitment of RNA polymerase 2 through chromatin immunoprecipitation (ChIP). Furthermore, an assay for transposase accessible chromatin (ATAC)-qPCR showed that hnRNP K induced higher chromatin accessibility within the RORγ1 and RORγ2 promoter. Then we found that the knockdown of hnRNP K lowers RORγ mRNA oscillation amplitude in both RORγ and RORγ-dependent metabolic genes. Moreover, we demonstrated that time-dependent extracellular signal-regulated kinase (ERK) activation controls mRNA oscillation of RORγ and RORγ-dependent metabolic genes through hnRNP K. Taken together, our results provide new insight into the regulation of RORγ by hnRNP K as a transcriptional activator, along with its physiological significance in metabolism.

Circadian gene expression is defined by the gene-specific phase and amplitude of daily oscillations in mRNA and protein levels. D site-binding protein mRNA (Dbp mRNA) shows high-amplitude oscillation; however, the underlying mechanism remains elusive. Here, we demonstrate that heterogeneous nuclear ribonucleoprotein K (hnRNP K) is a key regulator that activates Dbp transcription via the poly(C) motif within its proximal promoter. Biochemical analyses identified hnRNP K as a specific protein that directly associates with the poly(C) motif in vitro Interestingly, we further confirmed the rhythmic binding of endogenous hnRNP K within the Dbp promoter through chromatin immunoprecipitation as well as the cycling expression of hnRNP K. Finally, knockdown of hnRNP K decreased mRNA oscillation in both Dbp and Dbp-dependent clock genes. Taken together, our results show rhythmic protein expression of hnRNP K and provide new insights into its function as a transcriptional amplifier of Dbp.

Circadian gene expression is defined by the gene-specific phase and amplitude of daily oscillations in mRNA and protein levels. D site-binding protein mRNA (Dbp mRNA) shows high-amplitude oscillation; however, the underlying mechanism remains elusive. Here, we demonstrate that heterogeneous nuclear ribonucleoprotein K (hnRNP K) is a key regulator that activates Dbp transcription via the poly(C) motif within its proximal promoter. Biochemical analyses identified hnRNP K as a specific protein that directly associates with the poly(C) motif in vitro. Interestingly, we further confirmed the rhythmic binding of endogenous hnRNP K within the Dbp promoter through chromatin immunoprecipitation as well as the cycling expression of hnRNP K. Finally, knockdown of hnRNP K decreased mRNA oscillation in both Dbp and Dbp-dependent clock genes. Taken together, our results show rhythmic protein expression of hnRNP K and provide new insights into its function as a transcriptional amplifier of Dbp.

Zinc-oxide (ZnO) is widely used as an n-type electron transporting layer (ETL) for quantum dot (QD) light-emitting diode (QLED) because various metal doping can be possible and ZnO nanoparticle can be processed at low temperatures. We report here a Li- and Mg-doped ZnO, MLZO, which is used for ETL of highly efficient and long lifetime QLEDs. Co-doping, Mg and Li, in ZnO increases its band gap and electrical resistivity and thus can enhance charge balance in emission layer (EML). It is found also that the O–H concentration at the oxide surface decreases and exciton decay time of QDs on the metal oxide increases by co-doping in ZnO. The inverted green QLEDs with MLZO ETL exhibits the maximum current efficiency (CEmax) of 69.1 cd/A, power efficiency (PEmax) of 73.8 lm/W, and external quantum efficiency (EQEmax) of 18.4%. This is at least two times higher compared with the efficiencies of the QLEDs with Mg-doped ZnO ETL. The optimum Li and Mg concentrations are found to be 10% each. The deep-red, red, light-b...

We report a low work function (2.81 eV), Rb2CO3-doped polyethyleneimine ethoxylated (PEIE) which is used for highly efficient and long-lifetime, inverted organic light-emitting diodes (OLEDs). Doping Rb2CO3 into PEIE decreases the work function of Li-doped ZnO (LZO) by 1.0 eV and thus significantly improves electron injection ability into the emission layer (EML). The inverted OLED with PEIE:Rb2CO3 interfacial layer (IL) exhibits higher efficiency and longer operation lifetime than those of the device with a PEIE IL. It is found also that Mg-doped ZnO (MZO) can be used instead of LZO as electron transporting layer. MZO/PEIE:Rb2CO3 shows a low work function of 2.81 eV. The OLED with MZO/PEIE:Rb2CO3 exhibits low operating voltage of 5.0 V at 1000 cd m–2 and low efficiency roll-off of 11.8% at high luminance of 10 000 cd m–2. The results are due to the suppressed exciton quenching at the MZO/organic EML interface.

Charge generation junction (CGJ) is widely used in tandem organic light emitting diodes (OLEDs), mainly fabricated by vacuum deposition. But solution processed CGJs are used for quantum-dot light emitting diodes (QLEDs). It is demonstrated in this work that the QLEDs with top and bottom CGJs have similar device performance with conventional QLED. The current and power efficiencies of the QLED with top and bottom CGLs are almost independent on the work function of cathode metal, which demonstrates the effectiveness of the CGJs. Double stack QLED is designed and fabricated with the same three CGJs with 3 kinds of materials and two different quantum-dots materials.

We report in this wok the improvement of current efficiency (CE) roll-off and power efficiency (PE) roll-off of QLED by shell engineering of quantum-dots (QDs). The inverted QLEDs using the green QDs (G-QDs) with optimized shell exhibited the extremely reduced CE roll-off of 9% at 10,000 cd/m2 and also 10 times longer lifetime compared with the QLED with conventional G-QDs.

Astrocytes, the most representative glial cells in the brain, play a multitude of crucial functions for proper neuronal development and synaptic-network formation, including neuroprotection as well as physical and chemical support. However, little attention has been paid, in the neuroregenerative medicine and related fields, to the cytoprotective incorporation of astrocytes into neuron-culture scaffolds and full-fledged functional utilization of encapsulated astrocytes for controlled neuronal development. In this article, a 3D neurosupportive culture system for enhanced induction of neuronal circuit generation is reported, where astrocytes are confined in hydrogel microfibers and protected from the outside. The astrocyte-encapsulated microfibers significantly accelerate the neurite outgrowth and guide its directionality, and enhance the synaptic formation, without any physical contact with the neurons. This astrocyte-laden system provides a pivotal culture scaffold for advanced development of cell-based therapeutics for neural injuries, such as spinal cord injury.

The D site-binding protein (Dbp) supports the rhythmic transcription of downstream genes, in part by displaying high-amplitude cycling of its own transcripts compared to other circadian-clock genes. However, the underlying mechanism remains elusive. Here, we demonstrated that the poly(C) motif within the Dbp proximal promoter, in addition to an E-box element, provoked transcriptional activation. Furthermore, we generated a cell line with poly(C) deleted to demonstrate the endogenous effect of the poly(C) motif within the Dbp promoter. We investigated whether RNA polymerase 2 (Pol2) recruitment on the Dbp promoter was decreased in the cell line with poly(C) deleted. Next, assay for transposase-accessible chromatin (ATAC)-quantitative PCR (qPCR) showed that the poly(C) motif induced greater chromatin accessibility within the region of the Dbp promoter. Finally, we determined that the oscillation amplitude of endogenous Dbp mRNA of the cell line with poly(C) deleted was decreased, which affected the oscillation of other clock genes that are controlled by Dbp Taken together, our results provide new insights into the function of the poly(C) motif as a novel cis-acting element of Dbp, along with its significance in the regulation of circadian rhythms.

The D site-binding protein (Dbp) supports the rhythmic transcription of downstream genes, in part by displaying high-amplitude cycling of its own transcripts compared to other circadian-clock genes. However, the underlying mechanism remains elusive. Here, we demonstrated that the poly(C) motif within the Dbp proximal promoter, in addition to an E-box element, provoked transcriptional activation. Furthermore, we generated a cell line with poly(C) deleted to demonstrate the endogenous effect of the poly(C) motif within the Dbp promoter. We investigated whether RNA polymerase 2 (Pol2) recruitment on the Dbp promoter was decreased in the cell line with poly(C) deleted. Next, assay for transposase-accessible chromatin (ATAC)-quantitative PCR (qPCR) showed that the poly(C) motif induced greater chromatin accessibility within the region of the Dbp promoter. Finally, we determined that the oscillation amplitude of endogenous Dbp mRNA of the cell line with poly(C) deleted was decreased, which affected the oscillation of other clock genes that are controlled by Dbp. Taken together, our results provide new insights into the function of the poly(C) motif as a novel cis-acting element of Dbp, along with its significance in the regulation of circadian rhythms.

D-site albumin promoter binding protein (DBP) supports the rhythmic transcription of downstream genes, in part by displaying high-amplitude cycling of its own transcripts compared to other circadian clock genes. However, the underlying mechanism remains elusive. Here, we demonstrated that poly(C) motif within DBP proximal promoters, in addition to an E-box element, provoked the transcriptional activation through increased RNA polymerase 2 (Pol2) recruitment by inducing higher chromatin accessibility. We also clarified that heterogeneous nuclear ribonucleoprotein K (hnRNP K) is a key regulator that binds to the poly(C) motif on single-stranded DNAs in vitro. Chromatin immunoprecipitation further confirmed the expression-dependent and rhythmic binding of hnRNP K which was inhibited through its cytosolic localization mediated by time-dependent ERK activation. Knockdown of hnRNP K triggered low-amplitude mRNA rhythms in DBP and other core clock genes through transcriptional or post-transcriptional regulation. Finally, transgenic depletion of aDrosophilahomolog of hnRNP K in circadian pacemaker neurons lengthened 24-hour periodicity in free-running locomotor behaviors. Taken together, our results provide new insights into the function of hnRNP K as a transcriptional amplifier of DBP, which acts rhythmically through its intracellular localization by the ERK phosphorylation and as an mRNA stabilizer along with its physiological significance in circadian rhythms ofDrosophila.Significance StatementIn the case of mood disorders and the aging process, the mRNA expression and amplitude level of clock genes, including DBP, were reported to be diminished. However, the reason behind this decrease of clock gene amplitude and expression level remained unclear. Through this study, we revealed the regulatory mechanism behind the expression of clock genes, especially of DBP mRNA expression. In addition, we discovered that hnRNP K regulates more core clock genes than what we have previously known, such as Clock and Periods. Finally, we demonstrated the physiological significance of hnRNP K in Drosophila through its RNAi line model. Hence, our findings show the regulatory mechanism of circadian rhythm that may provide insight on mood disorder and aging process.

An inverted tandem quantum-dot light-emitting diode (QLEDs) is demonstrated using solution processed charge generation layers (CGLs) for the first time. The tandem QLEDs with the CGL, consisting of green QDs (G-QDs) for bottom and red QDs (R-QDs) for top cells, exhibited yellow emission with current efficiency of 15.9 cd/A at 1,000 cd/m2.