Sensitive detection of near-infrared (NIR) light is applicable to variety of optical, chemical, and biomedical sensors. Of these diverse applications, NIR photodetectors have been used as a key component for photoplethysmography (PPG) sensors. In particular, because NIR organic photodetectors (OPDs) enable fabrication of stretchable and skin-conformal PPG sensors, they are attaining tremendously increasing interest in both academia and industry. Herein, we report strain-durable and highly sensitive NIR OPDs using an organic bulk heterojunction (BHJ) layer. For effective suppression of dark current, we employed BHJ combination consisting of PTB7-Th:Y6 which forms high energy barrier against transport-injected holes. The optimized OPDs exhibited high specific detectivity up to 2.2 × 1012 Jones at 800 nm. By constructing the devices on the parylene substrates, we successfully demonstrated stretchable NIR OPDs and high-performance skin-conformal PPG sensors.
Hepatocellular carcinoma (HCC) exhibits widespread epigenetic alterations, yet their impact on cis-regulatory elements (CREs) and retrotransposons remains poorly understood. Here, we present an integrated epigenomic and transcriptomic analysis of HCC tumors and matched tumor-adjacent normal tissues. We identified extensive DNA hypomethylation coupled with changes in histone modifications at partially methylated domains, CREs, and retrotransposons. These epigenetic aberrations were associated with dysregulated expression of genes involved in cell cycle regulation, immune response, and extracellular matrix organization. Notably, our findings revealed a novel mechanism for the transcriptional dysregulation of GPC3, a key HCC biomarker and immunotherapeutic target. We observed that GPC3 upregulation is driven by both the reactivation of a fetal liver super enhancer and hypomethylation of GPC3-associated CpG islands. Moreover, we found that DNA hypomethylation-driven aberrant expression of retrotransposons carries prognostic significance in HCC. Patients with high expression of a long non-coding RNA driven by a HERVE-int element exhibited more aggressive tumors, poorer clinical outcomes, and molecular features associated with favorable immunotherapy response. Together, our study provides a comprehensive resource for understanding the role of epigenetic dysregulation in HCC and identifies retrotransposon-associated transcripts as potential biomarkers.
Abstract Super-enhancers (SEs) are expansive regions of genomic DNA that regulate the expression of genes involved in cell identity and cell fate. Recently, we found that distinct modules within a murine SE regulate gene expression of master regulatory transcription factor Vsx2 in a developmental stage- and cell-type specific manner. Vsx2 is expressed in retinal progenitor cells as well as differentiated bipolar neurons and Müller glia. Mutations in VSX2 in humans and mice lead to microphthalmia due to a defect in retinal progenitor cell proliferation. Deletion of a single module within the Vsx2 SE leads to microphthalmia. Deletion of a separate module within the SE leads to a complete loss of bipolar neurons, yet the remainder of the retina develops normally. Furthermore, the Vsx2 SE is evolutionarily conserved in vertebrates, suggesting that these modules are important for retinal development across species. In the present study, we examine the ability of these modules to drive retinal development between species. By inserting the human build of one Vsx2 SE module into a mouse with microphthalmia, eye size was rescued. To understand the implications of these SE modules in a model of human development, we generated human retinal organoids. Deleting one module results in small organoids, recapitulating the small-eyed phenotype of mice with microphthalmia, while deletion of the other module leads to a complete loss of ON cone bipolar neurons. This prototypical SE serves as a model for uncoupling developmental stage- and cell-type specific effects of neurogenic transcription factors with complex expression patterns. Moreover, by elucidating the gene regulatory mechanisms, we can begin to examine how dysregulation of these mechanisms contributes to phenotypic diversity and disease. Summary Statement Herein, we describe how conserved modules within a single super-enhancer can regulate VSX2 gene expression across species in both mice and human retinal organoids.
Chromatin assembled with centromere protein A (CENP-A) is the epigenetic mark of centromere identity. Using new reference models, we now identify sites of CENP-A and histone H3.1 binding within the megabase, α-satellite repeat–containing centromeres of 23 human chromosomes. The overwhelming majority (97%) of α-satellite DNA is found to be assembled with histone H3.1–containing nucleosomes with wrapped DNA termini. In both G1 and G2 cell cycle phases, the 2–4% of α-satellite assembled with CENP-A protects DNA lengths centered on 133 bp, consistent with octameric nucleosomes with DNA unwrapping at entry and exit. CENP-A chromatin is shown to contain equimolar amounts of CENP-A and histones H2A, H2B, and H4, with no H3. Solid-state nanopore analyses show it to be nucleosomal in size. Thus, in contrast to models for hemisomes that briefly transition to octameric nucleosomes at specific cell cycle points or heterotypic nucleosomes containing both CENP-A and histone H3, human CENP-A chromatin complexes are octameric nucleosomes with two molecules of CENP-A at all cell cycle phases.
Abstract Whole-genome sequencing is identifying growing numbers of non-coding variants in human disease studies, but the lack of accurate functional annotations prevents their interpretation. We describe the genome-wide landscape of distant-acting enhancers active in the developing and adult human heart, an organ whose impairment is a predominant cause of mortality and morbidity. Using integrative analysis of >35 epigenomic data sets from mouse and human pre- and postnatal hearts we created a comprehensive reference of >80,000 putative human heart enhancers. To illustrate the importance of enhancers in the regulation of genes involved in heart disease, we deleted the mouse orthologs of two human enhancers near cardiac myosin genes. In both cases, we observe in vivo expression changes and cardiac phenotypes consistent with human heart disease. Our study provides a comprehensive catalogue of human heart enhancers for use in clinical whole-genome sequencing studies and highlights the importance of enhancers for cardiac function.
This study was to investigate the anti-inflammatory effect of chicken-feet, Acathopanax, and Eucommia ulmoides Oliver mixture (CAEM) extract against lipopolysaccharide (LPS) in RAW 264.7 macrophage cells. We examined cytotoxicity of CAEM extract on RAW 264.7 cells, and their anti-inflammatory properties by measuring nitric oxide (NO) and pro-inflammatory cytokine production. In addition, inflammation-related gene expression was analyzed by real time-PCR in LPS-stimulated RAW 264.7 macrophage cells. Treatment of CAEM extract at concentrations of 0.31-2.5 mg/mL did not have any cytotoxic effect in RAW 264.7 cells. Treatment of LPS significantly increased the NO production, whereas CAEM extract (1.25, 2.5mg/mL) significantly decreased the levels of NO, compared to only LPS-treated cells. Furthermore, treatment with CAEM extract significantly suppressed the LPS-induced interleukin (IL)-6 and tumor necrosis factor-α (TNF-α) production. In order to confirm whether CAEM extract regulates inflammation-related gene expression, we analyzed the mRNA levels of IL-6, TNF-α, IL-1β, and inducible NO synthase (iNOS) by real time-PCR. Exposure of RAW 264.7 cells on LPS upregulated the mRNA levels of IL-6, TNF-α, IL-1β, and iNOS, compared to control group. However, those of expression were downregulated by treatment with CAEM extract. These findings suggest that CAEM extract may contribute to the prevention and treatment of inflammatory-related diseases.
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