Publications by authors named "Jonghwan Kim"

91 Publications

Amelioration of alcohol‑induced gastric mucosa damage by oral administration of food‑polydeoxyribonucleotides.

Mol Med Rep 2021 11 10;24(5). Epub 2021 Sep 10.

Research Strategy Team, C&D Center, Pharma Research, Seongnam, Gyeonggi‑do 13486, Republic of Korea.

Gastritis refers to inflammation caused by injury to the gastric epithelium, which is usually due to excessive alcohol consumption and prolonged use of nonsteroidal anti‑inflammatory drugs. Millions of individuals worldwide suffer from this disease. However, the lack of safe and promising treatments makes it urgent to explore and develop leads from natural resources. Therefore, food as medicine may be the best approach for the treatment of these disorders. The present study described the protective effects of food‑polydeoxyribonucleotides (f‑PDRNs) in a rat model of gastric mucosal injury induced by HCl‑EtOH. Administration of f‑PDRN was performed with low‑PRF002 (26 mg/kg/day), medium‑PRF002 (52 mg/kg/day) and high‑PRF002 (78 mg/kg/day) on the day of autopsy. The site of damage to the mucous membrane was also analysed. In addition, an increase in gastric juice pH, total acidity of gastric juice and decrease in gastric juice secretion were confirmed, and gastric juice secretion‑related factors corresponding to the administration of f‑PDRN were analysed. Administration of f‑PDRN reduced the mRNA expression of histamine H2 receptor, muscarinic acetylcholine receptor M3, cholecystokinin 2 receptor and H/K ATPase related to gastric acid secretion and downregulation of histamine, myeloperoxidase and cyclic adenosine monophosphate. In addition, it was histologically confirmed that the loss of epithelial cells and the distortion of the mucosa were recovered in the group in which f‑PDRN was administered compared to the model group with gastric mucosa damage. In summary, the present study suggested that f‑PDRN has therapeutic potential and may have beneficial effects if taken regularly as a food supplement.
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http://dx.doi.org/10.3892/mmr.2021.12430DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8441963PMC
November 2021

Release of Notch activity coordinated by IL-1β signalling confers differentiation plasticity of airway progenitors via Fosl2 during alveolar regeneration.

Nat Cell Biol 2021 09 2;23(9):953-966. Epub 2021 Sep 2.

Wellcome-MRC Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge, UK.

While the acquisition of cellular plasticity in adult stem cells is essential for rapid regeneration after tissue injury, little is known about the underlying mechanisms governing this process. Our data reveal the coordination of airway progenitor differentiation plasticity by inflammatory signals during alveolar regeneration. Following damage, interleukin-1β (IL-1β) signalling-dependent modulation of Jag1 and Jag2 expression in ciliated cells results in the inhibition of Notch signalling in secretory cells, which drives the reprogramming and acquisition of differentiation plasticity. We identify the transcription factor Fosl2 (also known as Fra2) for secretory cell fate conversion to alveolar type 2 cells that retain the distinct genetic and epigenetic signatures of secretory lineages. We also reveal that human secretory cells positive for KDR (also known as FLK-1) display a conserved capacity to generate alveolar type 2 cells via Notch inhibition. Our results demonstrate the functional role of an IL-1β-Notch-Fosl2 axis in the fate decision of secretory cells during injury repair, proposing a potential therapeutic target for human lung alveolar regeneration.
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http://dx.doi.org/10.1038/s41556-021-00742-6DOI Listing
September 2021

LC-ESI-MS/MS Simultaneous Analysis Method Coupled with Cation-Exchange Solid-Phase Extraction for Determination Of Pyrrolizidine Alkaloids on 5 Kinds of Herbal Medicines.

J AOAC Int 2021 Jul 23. Epub 2021 Jul 23.

Herbal Medicine Research Division, National Institute of Food and Drug Safety Evaluation, Chungbuk, 28159, Republic of Korea.

Background: Pyrrolizidine alkaloids (PAs) are naturally occurring plant toxins associated with potential hepatic and carcinogenic diseases in humans and animals. The concern of PAs has been increased as the consumption of herbal medicines is increased.

Objective: This study aimed to develop and validate a sensitive analytical method to determine 28 PAs in 5 herbal medicines using liquid chromatography-electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS). Additionally, this study identified and quantified the amount of PA in 10 samples of each herbal medicine.

Methods: The pretreatment in the proposed LC-MS/MS analysis comprised solvent extraction using 0.05M H2SO4 in 50% methanol and clean-up step by MCX-solid-phase extraction (SPE) cartridge. The PA contents in herbal medicines were measured by using the developed method.

Results: The proposed method had recoveries ranged from 72.5% ∼ 123.7% for the Atractylodis Rhizoma Alba, 70.6% ∼ 151.7% for Alba Chrysanthmi Flos, 80.6% ∼ 130.9% for Leonuri Herba, 70.3% ∼ 122.9% for Gastrodiae Rhizoma, and 67.1% ∼ 106.9% for Glycyrrhizae Radix. Even though a few samples showed recoveries in unsatisfactory values, the proposed method indicated entirely sufficient recoveries and precisions in most samples. In monitoring results, only Leonuri Herba contained two PAs, which indicated Retrorsine (4/10) of 84.7 ∼ 120.9 μg/kg and Senkirkine (10/10) of 60.9 ∼ 170.7 μg/kg.

Conclusions And Highlights: As the proposed method is revealed to be a reliable procedure for monitoring 28 PAs in herbal medicines, it seems to contribute to controlling the risks coming from pyrrolizidine alkaloids in certain medicinal plants and dietary supplements.
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http://dx.doi.org/10.1093/jaoacint/qsab098DOI Listing
July 2021

Heteroepitaxial van der Waals semiconductor superlattices.

Nat Nanotechnol 2021 Oct 15;16(10):1092-1098. Epub 2021 Jul 15.

Center for Artificial Low Dimensional Electronic Systems, Institute for Basic Science (IBS), Pohang, Korea.

A broad range of transition metal dichalcogenide (TMDC) semiconductors are available as monolayer (ML) crystals, so the precise integration of each kind into van der Waals (vdW) superlattices (SLs) could enable the realization of novel structures with previously unexplored functionalities. Here we report the atomic layer-by-layer epitaxial growth of vdW SLs with programmable stacking periodicities, composed of more than two kinds of dissimilar TMDC MLs, such as MoS, WS and WSe. Using kinetics-controlled vdW epitaxy in the near-equilibrium limit by metal-organic chemical vapour depositions, we achieved precise ML-by-ML stacking, free of interlayer atomic mixing, which resulted in tunable two-dimensional vdW electronic systems. As an example, by exploiting the series of type II band alignments at coherent two-dimensional vdW heterointerfaces, we demonstrated valley-polarized carrier excitations-one of the most distinctive electronic features in vdW ML semiconductors-which scale with the stack numbers n in our (MoS/WS) SLs on optical excitations.
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http://dx.doi.org/10.1038/s41565-021-00942-zDOI Listing
October 2021

Integrating High-Throughput Approaches and Human Trophoblast Models to Decipher Mechanisms Underlying Early Human Placenta Development.

Front Cell Dev Biol 2021 2;9:673065. Epub 2021 Jun 2.

Department of Molecular Biosciences, Center for Systems and Synthetic Biology, The University of Texas at Austin, Austin, TX, United States.

The placenta is a temporary but pivotal organ for human pregnancy. It consists of multiple specialized trophoblast cell types originating from the trophectoderm of the blastocyst stage of the embryo. While impaired trophoblast differentiation results in pregnancy disorders affecting both mother and fetus, the molecular mechanisms underlying early human placenta development have been poorly understood, partially due to the limited access to developing human placentas and the lack of suitable human trophoblast models. Recent success in establishing human trophoblast stem cells and other human trophoblast models with their differentiation protocols into more specialized cell types, such as syncytiotrophoblast and extravillous trophoblast, has provided a tremendous opportunity to understand early human placenta development. Unfortunately, while high-throughput research methods and omics tools have addressed numerous molecular-level questions in various research fields, these tools have not been widely applied to the above-mentioned human trophoblast models. This review aims to provide an overview of various omics approaches that can be utilized in the study of human placenta models by exemplifying some important lessons obtained from omics studies of mouse model systems and introducing recently available human trophoblast model systems. We also highlight some key unknown questions that might be addressed by such techniques. Integrating high-throughput omics approaches and human model systems will facilitate our understanding of molecular-level regulatory mechanisms underlying early human placenta development as well as placenta-associated complications.
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http://dx.doi.org/10.3389/fcell.2021.673065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8206641PMC
June 2021

Superconductivity emerging from a stripe charge order in IrTe nanoflakes.

Nat Commun 2021 May 26;12(1):3157. Epub 2021 May 26.

Center for Artificial Low Dimensional Electronic Systems, Institute for Basic Science, Pohang, Korea.

Superconductivity in the vicinity of a competing electronic order often manifests itself with a superconducting dome, centered at a presumed quantum critical point in the phase diagram. This common feature, found in many unconventional superconductors, has supported a prevalent scenario in which fluctuations or partial melting of a parent order are essential for inducing or enhancing superconductivity. Here we present a contrary example, found in IrTe nanoflakes of which the superconducting dome is identified well inside the parent stripe charge ordering phase in the thickness-dependent phase diagram. The coexisting stripe charge order in IrTe nanoflakes significantly increases the out-of-plane coherence length and the coupling strength of superconductivity, in contrast to the doped bulk IrTe. These findings clarify that the inherent instabilities of the parent stripe phase are sufficient to induce superconductivity in IrTe without its complete or partial melting. Our study highlights the thickness control as an effective means to unveil intrinsic phase diagrams of correlated van der Waals materials.
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http://dx.doi.org/10.1038/s41467-021-23310-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8154908PMC
May 2021

Author Correction: Direct observation of excitonic instability in TaNiSe.

Nat Commun 2021 May 14;12(1):2998. Epub 2021 May 14.

Department of Physics, Pohang University of Science and Technology, Pohang, South Korea.

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http://dx.doi.org/10.1038/s41467-021-23476-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8121826PMC
May 2021

γ-GeSe: A New Hexagonal Polymorph from Group IV-VI Monochalcogenides.

Nano Lett 2021 May 10;21(10):4305-4313. Epub 2021 May 10.

Department of Physics, Yonsei University, Seoul 03722, Korea.

The family of group IV-VI monochalcogenides has an atomically puckered layered structure, and their atomic bond configuration suggests the possibility for the realization of various polymorphs. Here, we report the synthesis of the first hexagonal polymorph from the family of group IV-VI monochalcogenides, which is conventionally orthorhombic. Recently predicted four-atomic-thick hexagonal GeSe, so-called γ-GeSe, is synthesized and clearly identified by complementary structural characterizations, including elemental analysis, electron diffraction, high-resolution transmission electron microscopy imaging, and polarized Raman spectroscopy. The electrical and optical measurements indicate that synthesized γ-GeSe exhibits high electrical conductivity of 3 × 10 S/m, which is comparable to those of other two-dimensional layered semimetallic crystals. Moreover, γ-GeSe can be directly grown on h-BN substrates, demonstrating a bottom-up approach for constructing vertical van der Waals heterostructures incorporating γ-GeSe. The newly identified crystal symmetry of γ-GeSe warrants further studies on various physical properties of γ-GeSe.
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http://dx.doi.org/10.1021/acs.nanolett.1c00714DOI Listing
May 2021

The complete chloroplast genome sequence of three medicinal species; and (Zingiberaceae).

Mitochondrial DNA B Resour 2021 Apr 8;6(4):1363-1364. Epub 2021 Apr 8.

Herbal Medicine Research Division, National Institute of Food and Drug Safety Evaluation, Ministry of Food and Drug Safety, Cheongju-si, Republic of Korea.

and are important herbal medicine which of rhizomatous herbaceous perennial plant of the family Zingiberaceae. This study generated a complete chloroplast genome sequence of three medicinal species were characterized by de novo assembly with whole genome sequencing data. The length of complete chloroplast genome were 162,180 bp (), 162,266 bp (), and 162,133 bp (), respectively, with four structures that were included in large single copy region (87,001 bp, 87,042 bp, and 87,013 bp), small single copy region (15,681 bp, 15,710 bp, and 15,622 bp), and duplicated inverted regions (29,749 bp, 29,757 bp and 29,749 bp of each). Based on phylogenetic trees, and were grouped by high bootstrap value with species. This result approved that and were comprised in . Therefore, this chloroplast genome data firstly generated valuable genetic resource in discrimination of herbal materials, phylogeny and development DNA marker.
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http://dx.doi.org/10.1080/23802359.2020.1768917DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8043548PMC
April 2021

Direct observation of excitonic instability in TaNiSe.

Nat Commun 2021 Mar 30;12(1):1969. Epub 2021 Mar 30.

Department of Physics, Pohang University of Science and Technology, Pohang, South Korea.

Coulomb attraction between electrons and holes in a narrow-gap semiconductor or a semimetal is predicted to lead to an elusive phase of matter dubbed excitonic insulator. However, direct observation of such electronic instability remains extremely rare. Here, we report the observation of incipient divergence in the static excitonic susceptibility of the candidate material TaNiSe using Raman spectroscopy. Critical fluctuations of the excitonic order parameter give rise to quasi-elastic scattering of B symmetry, whose intensity grows inversely with temperature toward the Weiss temperature of T ≈ 237 K, which is arrested by a structural phase transition driven by an acoustic phonon of the same symmetry at T = 325 K. Concurrently, a B optical phonon becomes heavily damped to the extent that its trace is almost invisible around T, which manifests a strong electron-phonon coupling that has obscured the identification of the low-temperature phase as an excitonic insulator for more than a decade. Our results unambiguously reveal the electronic origin of the phase transition.
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http://dx.doi.org/10.1038/s41467-021-22133-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8010035PMC
March 2021

The oncogene AAMDC links PI3K-AKT-mTOR signaling with metabolic reprograming in estrogen receptor-positive breast cancer.

Nat Commun 2021 03 26;12(1):1920. Epub 2021 Mar 26.

Centre for Medical Research, The University of Western Australia, Perth, WA, Australia.

Adipogenesis associated Mth938 domain containing (AAMDC) represents an uncharacterized oncogene amplified in aggressive estrogen receptor-positive breast cancers. We uncover that AAMDC regulates the expression of several metabolic enzymes involved in the one-carbon folate and methionine cycles, and lipid metabolism. We show that AAMDC controls PI3K-AKT-mTOR signaling, regulating the translation of ATF4 and MYC and modulating the transcriptional activity of AAMDC-dependent promoters. High AAMDC expression is associated with sensitization to dactolisib and everolimus, and these PI3K-mTOR inhibitors exhibit synergistic interactions with anti-estrogens in IntClust2 models. Ectopic AAMDC expression is sufficient to activate AKT signaling, resulting in estrogen-independent tumor growth. Thus, AAMDC-overexpressing tumors may be sensitive to PI3K-mTORC1 blockers in combination with anti-estrogens. Lastly, we provide evidence that AAMDC can interact with the RabGTPase-activating protein RabGAP1L, and that AAMDC, RabGAP1L, and Rab7a colocalize in endolysosomes. The discovery of the RabGAP1L-AAMDC assembly platform provides insights for the design of selective blockers to target malignancies having the AAMDC amplification.
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http://dx.doi.org/10.1038/s41467-021-22101-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7998036PMC
March 2021

Conserved dual-mode gene regulation programs in higher eukaryotes.

Nucleic Acids Res 2021 03;49(5):2583-2597

Davis Center for Regenerative Biology and Medicine, MDI Biological Laboratory, Bar Harbor, ME 04609, USA.

Recent genomic data analyses have revealed important underlying logics in eukaryotic gene regulation, such as CpG islands (CGIs)-dependent dual-mode gene regulation. In mammals, genes lacking CGIs at their promoters are generally regulated by interconversion between euchromatin and heterochromatin, while genes associated with CGIs constitutively remain as euchromatin. Whether a similar mode of gene regulation exists in non-mammalian species has been unknown. Here, through comparative epigenomic analyses, we demonstrate that the dual-mode gene regulation program is common in various eukaryotes, even in the species lacking CGIs. In cases of vertebrates or plants, we find that genes associated with high methylation level promoters are inactivated by forming heterochromatin and expressed in a context-dependent manner. In contrast, the genes with low methylation level promoters are broadly expressed and remain as euchromatin even when repressed by Polycomb proteins. Furthermore, we show that invertebrate animals lacking DNA methylation, such as fruit flies and nematodes, also have divergence in gene types: some genes are regulated by Polycomb proteins, while others are regulated by heterochromatin formation. Altogether, our study establishes gene type divergence and the resulting dual-mode gene regulation as fundamental features shared in a broad range of higher eukaryotic species.
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http://dx.doi.org/10.1093/nar/gkab108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7969006PMC
March 2021

Context-dependent roles of YAP/TAZ in stem cell fates and cancer.

Cell Mol Life Sci 2021 May 13;78(9):4201-4219. Epub 2021 Feb 13.

Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX, 78712, USA.

Hippo effectors YAP and TAZ control cell fate and survival through various mechanisms, including transcriptional regulation of key genes. However, much of this research has been marked by conflicting results, as well as controversy over whether YAP and TAZ are redundant. A substantial portion of the discordance stems from their contradictory roles in stem cell self-renewal vs. differentiation and cancer cell survival vs. apoptosis. In this review, we present an overview of the multiple context-dependent functions of YAP and TAZ in regulating cell fate decisions in stem cells and organoids, as well as their mechanisms of controlling programmed cell death pathways in cancer.
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http://dx.doi.org/10.1007/s00018-021-03781-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8164607PMC
May 2021

Mechanobiological conditioning of mesenchymal stem cells for enhanced vascular regeneration.

Nat Biomed Eng 2021 01 22;5(1):89-102. Epub 2021 Jan 22.

Department of Biomedical Engineering, University of Texas at Austin, Austin, TX, USA.

Using endogenous mesenchymal stem cells for treating myocardial infarction and other cardiovascular conditions typically results in poor efficacy, in part owing to the heterogeneity of the harvested cells and of the patient responses. Here, by means of high-throughput screening of the combinatorial space of mechanical-strain level and of the presence of particular kinase inhibitors, we show that human mesenchymal stem cells can be mechanically and pharmacologically conditioned to enhance vascular regeneration in vivo. Mesenchymal stem cells conditioned to increase the activation of signalling pathways mediated by Smad2/3 (mothers against decapentaplegic homolog 2/3) and YAP (Yes-associated protein) expressed markers that are associated with pericytes and endothelial cells, displayed increased angiogenic activity in vitro, and enhanced the formation of vasculature in mice after subcutaneous implantation and after implantation in ischaemic hindlimbs. These effects were mediated by the crosstalk of endothelial-growth-factor receptors, transforming-growth-factor-beta receptor type 1 and vascular-endothelial-growth-factor receptor 2. Mechanical and pharmacological conditioning can significantly enhance the regenerative properties of mesenchymal stem cells.
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http://dx.doi.org/10.1038/s41551-020-00674-wDOI Listing
January 2021

Author Correction: Evidence of higher-order topology in multilayer WTe from Josephson coupling through anisotropic hinge states.

Nat Mater 2020 Sep;19(9):1036

Department of Physics, Pohang University of Science and Technology, Pohang, Republic of Korea.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41563-020-0762-0DOI Listing
September 2020

Evidence of higher-order topology in multilayer WTe from Josephson coupling through anisotropic hinge states.

Nat Mater 2020 Sep 6;19(9):974-979. Epub 2020 Jul 6.

Department of Physics, Pohang University of Science and Technology, Pohang, Republic of Korea.

Td-WTe (non-centrosymmetric and orthorhombic), a type-II Weyl semimetal, is expected to have higher-order topological phases with topologically protected, helical one-dimensional hinge states when its Weyl points are annihilated. However, the detection of these hinge states is difficult due to the semimetallic behaviour of the bulk. In this study, we have spatially resolved the hinge states by analysing the magnetic field interference of the supercurrent in Nb-WTe-Nb proximity Josephson junctions. The Josephson current along the a axis of the WTe crystal, but not along the b axis, showed a sharp enhancement at the edges of the junction, and the amount of enhanced Josephson current was comparable to the upper limits of a single one-dimensional helical channel. Our experimental observations suggest a higher-order topological phase in WTe and its corresponding anisotropic topological hinge states, in agreement with theoretical calculations. Our work paves the way for the study of hinge states in topological transition-metal dichalcogenides and analogous phases.
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http://dx.doi.org/10.1038/s41563-020-0721-9DOI Listing
September 2020

Systematic Discovery of Endogenous Human Ribonucleoprotein Complexes.

Cell Rep 2019 10;29(5):1351-1368.e5

Department of Molecular Biosciences, University of Texas at Austin, Austin, TX 78712, USA; Center for Systems and Synthetic Biology, University of Texas at Austin, Austin, TX 78712, USA; Institute for Cellular and Molecular Biology, University of Texas at Austin, Austin, TX 78712, USA. Electronic address:

RNA-binding proteins (RBPs) play essential roles in biology and are frequently associated with human disease. Although recent studies have systematically identified individual RNA-binding proteins, their higher-order assembly into ribonucleoprotein (RNP) complexes has not been systematically investigated. Here, we describe a proteomics method for systematic identification of RNP complexes in human cells. We identify 1,428 protein complexes that associate with RNA, indicating that more than 20% of known human protein complexes contain RNA. To explore the role of RNA in the assembly of each complex, we identify complexes that dissociate, change composition, or form stable protein-only complexes in the absence of RNA. We use our method to systematically identify cell-type-specific RNA-associated proteins in mouse embryonic stem cells and finally, distribute our resource, rna.MAP, in an easy-to-use online interface (rna.proteincomplexes.org). Our system thus provides a methodology for explorations across human tissues, disease states, and throughout all domains of life.
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http://dx.doi.org/10.1016/j.celrep.2019.09.060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6873818PMC
October 2019

Super-enhancer-guided mapping of regulatory networks controlling mouse trophoblast stem cells.

Nat Commun 2019 10 18;10(1):4749. Epub 2019 Oct 18.

Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX, 78712, USA.

Trophectoderm (TE) lineage development is pivotal for proper implantation, placentation, and healthy pregnancy. However, only a few TE-specific transcription factors (TFs) have been systematically characterized, hindering our understanding of the process. To elucidate regulatory mechanisms underlying TE development, here we map super-enhancers (SEs) in trophoblast stem cells (TSCs) as a model. We find both prominent TE-specific master TFs (Cdx2, Gata3, and Tead4), and >150 TFs that had not been previously implicated in TE lineage, that are SE-associated. Mapping targets of 27 SE-predicted TFs reveals a highly intertwined transcriptional regulatory circuitry. Intriguingly, SE-predicted TFs show 4 distinct expression patterns with dynamic alterations of their targets during TSC differentiation. Furthermore, depletion of a subset of TFs results in dysregulation of the markers for specialized cell types in placenta, suggesting a role during TE differentiation. Collectively, we characterize an expanded TE-specific regulatory network, providing a framework for understanding TE lineage development and placentation.
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http://dx.doi.org/10.1038/s41467-019-12720-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6802173PMC
October 2019

Atomically thin three-dimensional membranes of van der Waals semiconductors by wafer-scale growth.

Sci Adv 2019 Jul 26;5(7):eaaw3180. Epub 2019 Jul 26.

Center for Artificial Low Dimensional Electronic Systems, Institute for Basic Science (IBS), Pohang 37673, Republic of Korea.

We report wafer-scale growth of atomically thin, three-dimensional (3D) van der Waals (vdW) semiconductor membranes. By controlling the growth kinetics in the near-equilibrium limit during metal-organic chemical vapor depositions of MoS and WS monolayer (ML) crystals, we have achieved conformal ML coverage on diverse 3D texture substrates, such as periodic arrays of nanoscale needles and trenches on quartz and SiO/Si substrates. The ML semiconductor properties, such as channel resistivity and photoluminescence, are verified to be seamlessly uniform over the 3D textures and are scalable to wafer scale. In addition, we demonstrated that these 3D films can be easily delaminated from the growth substrates to form suspended 3D semiconductor membranes. Our work suggests that vdW ML semiconductor films can be useful platforms for patchable membrane electronics with atomic precision, yet large areas, on arbitrary substrates.
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http://dx.doi.org/10.1126/sciadv.aaw3180DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6660212PMC
July 2019

TAF5L and TAF6L Maintain Self-Renewal of Embryonic Stem Cells via the MYC Regulatory Network.

Mol Cell 2019 06 17;74(6):1148-1163.e7. Epub 2019 Apr 17.

Department of Anatomy and Developmental Biology, Monash University, Wellington Road, Clayton, VIC 3800, Australia; Development and Stem Cells Program, Monash Biomedicine Discovery Institute, Wellington Road, Clayton, VIC 3800, Australia. Electronic address:

Self-renewal and pluripotency of the embryonic stem cell (ESC) state are established and maintained by multiple regulatory networks that comprise transcription factors and epigenetic regulators. While much has been learned regarding transcription factors, the function of epigenetic regulators in these networks is less well defined. We conducted a CRISPR-Cas9-mediated loss-of-function genetic screen that identified two epigenetic regulators, TAF5L and TAF6L, components or co-activators of the GNAT-HAT complexes for the mouse ESC (mESC) state. Detailed molecular studies demonstrate that TAF5L/TAF6L transcriptionally activate c-Myc and Oct4 and their corresponding MYC and CORE regulatory networks. Besides, TAF5L/TAF6L predominantly regulate their target genes through H3K9ac deposition and c-MYC recruitment that eventually activate the MYC regulatory network for self-renewal of mESCs. Thus, our findings uncover a role of TAF5L/TAF6L in directing the MYC regulatory network that orchestrates gene expression programs to control self-renewal for the maintenance of mESC state.
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http://dx.doi.org/10.1016/j.molcel.2019.03.025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6671628PMC
June 2019

Author Correction: ZSCAN10 expression corrects the genomic instability of iPSCs from aged donors.

Nat Cell Biol 2019 04;21(4):531-532

Cancer Biology and Genetics Program, Center for Cell Engineering, Center for Stem Cell Biology, Memorial Sloan Kettering Cancer Center, Sloan Kettering Institute for Cancer Research, and Department of Cell and Developmental Biology, Weill Medical College of Cornell University, New York, New York, 10065, USA.

In the version of this Article originally published, Supplementary Fig. 6j showed incorrect values for the LS and AG4 glutathione samples, and Fig. 5c and Supplementary Fig. 6j did not include all n = 6 samples for the hESC, Y-hiPSC and AG4-ZSCAN10 groups as was stated in the legend. In addition, the bars for hESC, Y-hiPSC, AG4-ZCNAN10, AG4 and LS in Supplementary Fig. 6i and j have been reproduced from Fig. 5b and c, respectively. Fig. 6e was also reproduced in the lower panel of Supplementary Fig. 6h, to enable direct comparison of the data, however this was not explained in the original figure legends. The correct versions of these figures and their legends are shown below, and Supplementary Table 5 has been updated with the source data for all numerical data in the manuscript.
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http://dx.doi.org/10.1038/s41556-018-0269-yDOI Listing
April 2019

Yap1 safeguards mouse embryonic stem cells from excessive apoptosis during differentiation.

Elife 2018 12 18;7. Epub 2018 Dec 18.

Department of Molecular Biosciences, The University of Texas at Austin, Austin, United States.

Approximately, 30% of embryonic stem cells (ESCs) die after exiting self-renewal, but regulators of this process are not well known. Yap1 is a Hippo pathway transcriptional effector that plays numerous roles in development and cancer. However, its functions in ESC differentiation remain poorly characterized. We first reveal that ESCs lacking Yap1 experience massive cell death upon the exit from self-renewal. We subsequently show that Yap1 contextually protects differentiating, but not self-renewing, ESC from hyperactivation of the apoptotic cascade. Mechanistically, Yap1 strongly activates anti-apoptotic genes via regulatory elements while mildly suppressing pro-apoptotic genes, which moderates the level of mitochondrial priming that occurs during differentiation. Individually modulating the expression of single apoptosis-related genes targeted by Yap1 is sufficient to augment or hinder survival during differentiation. Our demonstration of the context-dependent pro-survival functions of Yap1 during ESC differentiation contributes to our understanding of the balance between survival and death during cell fate changes.
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http://dx.doi.org/10.7554/eLife.40167DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6307859PMC
December 2018

miRNA-mediated TUSC3 deficiency enhances UPR and ERAD to promote metastatic potential of NSCLC.

Nat Commun 2018 11 30;9(1):5110. Epub 2018 Nov 30.

Comprehensive Cancer Center, The Ohio State University, Columbus, OH, 43210, USA.

Non-small cell lung carcinoma (NSCLC) is leading cause of cancer-related deaths in the world. The Tumor Suppressor Candidate 3 (TUSC3) at chromosome 8p22 known to be frequently deleted in cancer is often found to be deleted in advanced stage of solid tumors. However, the role of TUSC3 still remains controversial in lung cancer and context-dependent in several cancers. Here we propose that miR-224/-520c-dependent TUSC3 deficiency enhances the metastatic potential of NSCLC through the alteration of three unfolded protein response pathways and HRD1-dependent ERAD. ATF6α-dependent UPR is enhanced whereas the affinity of HRD1 to its substrates, PERK, IRE1α and p53 is weakened. Consequently, the alteration of UPRs and the suppressed p53-NM23H1/2 pathway by TUSC3 deficiency is ultimately responsible for enhancing metastatic potential of lung cancer. These findings provide mechanistic insight of unrecognized roles of TUSC3 in cancer progression and the oncogenic role of HRD1-dependent ERAD in cancer metastasis.
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http://dx.doi.org/10.1038/s41467-018-07561-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6269493PMC
November 2018

Homeodomain Proteins Directly Regulate ATM Kinase Activity.

Cell Rep 2018 08;24(6):1471-1483

Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX 78712, USA; Howard Hughes Medical Institute, The University of Texas at Austin, Austin, TX 78712, USA. Electronic address:

Ataxia-telangiectasia mutated (ATM) is a serine/threonine kinase that coordinates the response to DNA double-strand breaks and oxidative stress. NKX3.1, a prostate-specific transcription factor, was recently shown to directly stimulate ATM kinase activity through its highly conserved homeodomain. Here, we show that other members of the homeodomain family can also regulate ATM kinase activity. We found that six representative homeodomain proteins (NKX3.1, NKX2.2, TTF1, NKX2.5, HOXB7, and CDX2) physically and functionally interact with ATM and with the Mre11-Rad50-Nbs1 (MRN) complex that activates ATM in combination with DNA double-strand breaks. The binding between homeodomain proteins and ATM stimulates oxidation-induced ATM activation in vitro but inhibits ATM kinase activity in the presence of MRN and DNA and in human cells. These findings suggest that many tissue-specific homeodomain proteins may regulate ATM activity during development and differentiation and that this is a unique mechanism for the control of the DNA damage response.
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http://dx.doi.org/10.1016/j.celrep.2018.06.089DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6127865PMC
August 2018

Tumor penetrating peptides inhibiting MYC as a potent targeted therapeutic strategy for triple-negative breast cancers.

Oncogene 2019 01 3;38(1):140-150. Epub 2018 Aug 3.

Harry Perkins Institute of Medical Research, QEII Medical Centre, Nedlands and Centre for Medical Research, The University of Western Australia, Crawley, WA, 6009, Australia.

Overexpression of MYC oncogene is highly prevalent in many malignancies such as aggressive triple-negative breast cancers (TNBCs) and it is associated with very poor outcome. Despite decades of research, attempts to effectively inhibit MYC, particularly with small molecules, still remain challenging due to the featureless nature of its protein structure. Herein, we describe the engineering of the dominant-negative MYC peptide (OmoMYC) linked to a functional penetrating 'Phylomer' peptide (FPPa) as a therapeutic strategy to inhibit MYC in TNBC. We found FPPa-OmoMYC to be a potent inducer of apoptosis (with IC from 1-2 µM) in TNBC cells with negligible effects in non-tumorigenic cells. Transcriptome analysis of FPPa-OmoMYC-treated cells indicated that the fusion protein inhibited MYC-dependent networks, inducing dynamic changes in transcriptional, metabolic, and apoptotic processes. We demonstrated the efficacy of FPPa-OmoMYC in inhibiting breast cancer growth when injected orthotopically in TNBC allografts. Lastly, we identified strong pharmacological synergisms between FPPa-OmoMYC and chemotherapeutic agents. This study highlights a novel therapeutic approach to target highly aggressive and chemoresistant MYC-activated cancers.
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http://dx.doi.org/10.1038/s41388-018-0421-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6318000PMC
January 2019

The role of momentum-dark excitons in the elementary optical response of bilayer WSe.

Nat Commun 2018 07 3;9(1):2586. Epub 2018 Jul 3.

Fakultät für Physik, Munich Quantum Center, and Center for NanoScience (CeNS), Ludwig-Maximilians-Universität München, Geschwister-Scholl-Platz 1, D-80539, München, Germany.

Monolayer transition metal dichalcogenides (TMDs) undergo substantial changes in the single-particle band structure and excitonic optical response upon the addition of just one layer. As opposed to the single-layer limit, the bandgap of bilayer (BL) TMD semiconductors is indirect which results in reduced photoluminescence with richly structured spectra that have eluded a detailed understanding to date. Here, we provide a closed interpretation of cryogenic emission from BL WSe as a representative material for the wider class of TMD semiconductors. By combining theoretical calculations with comprehensive spectroscopy experiments, we identify the crucial role of momentum-indirect excitons for the understanding of BL TMD emission. Our results shed light on the origin of quantum dot formation in BL crystals and will facilitate further advances directed at opto-electronic applications of layered TMD semiconductors in van der Waals heterostructures and devices.
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http://dx.doi.org/10.1038/s41467-018-04877-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6030057PMC
July 2018

Uhrf1 regulates active transcriptional marks at bivalent domains in pluripotent stem cells through Setd1a.

Nat Commun 2018 07 3;9(1):2583. Epub 2018 Jul 3.

Department of Genetics, Yale Stem Cell Center, Yale Child Study Center, Yale School of Medicine, New Haven, CT, 06520, USA.

Embryonic stem cells (ESCs) maintain pluripotency through unique epigenetic states. When ESCs commit to a specific lineage, epigenetic changes in histones and DNA accompany the transition to specialized cell types. Investigating how epigenetic regulation controls lineage specification is critical in order to generate the required cell types for clinical applications. Uhrf1 is a widely known hemi-methylated DNA-binding protein, playing a role in DNA methylation through the recruitment of Dnmt1 and in heterochromatin formation alongside G9a, Trim28, and HDACs. Although Uhrf1 is not essential in ESC self-renewal, it remains elusive how Uhrf1 regulates cell specification. Here we report that Uhrf1 forms a complex with the active trithorax group, the Setd1a/COMPASS complex, to maintain bivalent histone marks, particularly those associated with neuroectoderm and mesoderm specification. Overall, our data demonstrate that Uhrf1 safeguards proper differentiation via bivalent histone modifications.
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http://dx.doi.org/10.1038/s41467-018-04818-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6030064PMC
July 2018

Imaging of pure spin-valley diffusion current in WS-WSe heterostructures.

Science 2018 05 24;360(6391):893-896. Epub 2018 May 24.

Department of Physics, University of California at Berkeley, Berkeley, CA 94720, USA.

Transition metal dichalcogenide (TMDC) materials are promising for spintronic and valleytronic applications because valley-polarized excitations can be generated and manipulated with circularly polarized photons and the valley and spin degrees of freedom are locked by strong spin-orbital interactions. In this study we demonstrate efficient generation of a pure and locked spin-valley diffusion current in tungsten disulfide (WS)-tungsten diselenide (WSe) heterostructures without any driving electric field. We imaged the propagation of valley current in real time and space by pump-probe spectroscopy. The valley current in the heterostructures can live for more than 20 microseconds and propagate over 20 micrometers; both the lifetime and the diffusion length can be controlled through electrostatic gating. The high-efficiency and electric-field-free generation of a locked spin-valley current in TMDC heterostructures holds promise for applications in spin and valley devices.
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http://dx.doi.org/10.1126/science.aao3503DOI Listing
May 2018

Implications of CpG islands on chromosomal architectures and modes of global gene regulation.

Nucleic Acids Res 2018 05;46(9):4382-4391

Department of Molecular Biosciences, The University of Texas at Austin, Austin, Texas 78712, USA.

CpG islands (CGIs) have long been implicated in the regulation of vertebrate gene expression. However, the involvement of CGIs in chromosomal architectures and associated gene expression regulations has not yet been thoroughly explored. By combining large-scale integrative data analyses and experimental validations, we show that CGIs clearly reconcile two competing models explaining nuclear gene localizations. We first identify CGI-containing (CGI+) and CGI-less (CGI-) genes are non-randomly clustered within the genome, which reflects CGI-dependent spatial gene segregation in the nucleus and corresponding gene regulatory modes. Regardless of their transcriptional activities, CGI+ genes are mainly located at the nuclear center and encounter frequent long-range chromosomal interactions. Meanwhile, nuclear peripheral CGI- genes forming heterochromatin are activated and internalized into the nuclear center by local enhancer-promoter interactions. Our findings demonstrate the crucial implications of CGIs on chromosomal architectures and gene positioning, linking the critical importance of CGIs in determining distinct mechanisms of global gene regulation in three-dimensional space in the nucleus.
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http://dx.doi.org/10.1093/nar/gky147DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5961348PMC
May 2018

Comprehensive HPTLC Fingerprinting for Quality Control of an Herbal Drug - The Case of Angelica gigas Root.

Planta Med 2018 Apr 28;84(6-07):465-474. Epub 2018 Feb 28.

CAMAG Laboratory, Muttenz, Switzerland.

The quality of herbal drugs is usually controlled using several tests recommended in a monograph. HPTLC is the method of choice for identification in many pharmacopoeias. If combined with a suitable reference material for comparison, HPTLC can provide information beyond identification and thus may simplify quality control. This paper describes, as a proof of concept, how HPTLC can be applied to define specifications for an herbal reference material and to control the quality of an herbal drug according to these specifications. Based on multiple batches of cultivated root, a specific HPTLC method for identification was optimized. This method can distinguish 27 related species. It also can detect the presence of mixtures of with two other species traded as "Dang gui" and is suitable as well for quantitative assessment of samples in a test for minimum content of the sum of decursin and decursinol angelate. The new concept of "comprehensive HPTLC fingerprinting" is proposed: HPTLC fingerprints (images), which are used for identification, are converted into peak profiles and the intensities of selected zones are quantitatively compared to those of the corresponding zones of the reference material. Following a collaborative trial involving three laboratories in three countries, the method was applied to check the quality of further candidates for establishing an appropriate reference material. In conclusion, this case demonstrates that a single HPTLC analysis can provide information about identity, purity, and minimum content of markers of an herbal drug.
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http://dx.doi.org/10.1055/a-0575-4425DOI Listing
April 2018
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