Integrative approaches based on genomic techniques in the functional studies on enhancers.

With the development of sequencing technology and the dramatic drop in sequencing cost, the functions of noncoding genes are being characterized in a wide variety of fields (e.g. biomedicine). Enhancers are noncoding DNA elements with vital transcription regulation functions. Tens of thousands of enhancers have been identified in the human genome; however, the location, function, target genes and regulatory mechanisms of most enhancers have not been elucidated thus far. As high-throughput sequencing techniques have leapt forwards, omics approaches have been extensively employed in enhancer research. Multidimensional genomic data integration enables the full exploration of the data and provides novel perspectives for screening, identification and characterization of the function and regulatory mechanisms of unknown enhancers. However, multidimensional genomic data are still difficult to integrate genome wide due to complex varieties, massive amounts, high rarity, etc. To facilitate the appropriate methods for studying enhancers with high efficacy, we delineate the principles, data processing modes and progress of various omics approaches to study enhancers and summarize the applications of traditional machine learning and deep learning in multi-omics integration in the enhancer field. In addition, the challenges encountered during the integration of multiple omics data are addressed. Overall, this review provides a comprehensive foundation for enhancer analysis.

An oncogenic enhancer promotes melanoma progression via regulating ETV4 expression.

BACKGROUND: Enhancers are important gene regulatory elements that promote the expression of critical genes in development and disease. Aberrant enhancer can modulate cancer risk and activate oncogenes that lead to the occurrence of various cancers. However, the underlying mechanism of most enhancers in cancer remains unclear. Here, we aim to explore the function and mechanism of a crucial enhancer in melanoma. METHODS: Multi-omics data were applied to identify an enhancer (enh17) involved in melanoma progression. To evaluate the function of enh17, CRISPR/Cas9 technology were applied to knockout enh17 in melanoma cell line A375. RNA-seq, ChIP-seq and Hi-C data analysis integrated with luciferase reporter assay were performed to identify the potential target gene of enh17. Functional experiments were conducted to further validate the function of the target gene ETV4. Multi-omics data integrated with CUT&Tag sequencing were performed to validate the binding profile of the inferred transcription factor STAT3. RESULTS: An enhancer, named enh17 here, was found to be aberrantly activated and involved in melanoma progression. CRISPR/Cas9-mediated deletion of enh17 inhibited cell proliferation, migration, and tumor growth of melanoma both in vitro and in vivo. Mechanistically, we identified ETV4 as a target gene regulated by enh17, and functional experiments further support ETV4 as a target gene that is involved in cancer-associated phenotypes. In addition, STAT3 acts as a transcription factor binding with enh17 to regulate the transcription of ETV4. CONCLUSIONS: Our findings revealed that enh17 plays an oncogenic role and promotes tumor progression in melanoma, and its transcriptional regulatory mechanisms were fully elucidated, which may open a promising window for melanoma prevention and treatment.

The Mechanotransduction Signaling Pathways in the Regulation of Osteogenesis.

Bones are constantly exposed to mechanical forces from both muscles and Earth's gravity to maintain bone homeostasis by stimulating bone formation. Mechanotransduction transforms external mechanical signals such as force, fluid flow shear, and gravity into intracellular responses to achieve force adaptation. However, the underlying molecular mechanisms on the conversion from mechanical signals into bone formation has not been completely defined yet. In the present review, we provide a comprehensive and systematic description of the mechanotransduction signaling pathways induced by mechanical stimuli during osteogenesis and address the different layers of interconnections between different signaling pathways. Further exploration of mechanotransduction would benefit patients with osteoporosis, including the aging population and postmenopausal women.

Spin Selectivity of Chiral Mesostructured Iron Oxides with Different Magnetisms.

Spin selectivity physically depends on either magnetic materials with strong internal magnetic fields or symmetry-breaking materials with large spin-orbit coupling (SOC). However, the spin selectivity of symmetry-breaking magnetic materials is not understood. Herein, the spin selectivity of iron oxides with different magnetisms arising from varying spin alignment is investigated. Chiral mesostructured films of Fe3 O4 (CMFFs), γ-Fe2 O3 (CMγFs), and α-Fe2 O3 (CMαFs), which share the same mesostructure, are prepared by a controllable calcination process of chiral mesostructured FeOOH films (CMOFs) grown on the substrate via an amino acid-induced hydrothermal route. CMFFs and CMγFs with ferrimagnetism exhibit magnetic field-dependent and simultaneously chirality-independent magnetic circular dichroism (MCD) signals, while CMαFs with antiferromagnetism exhibit chirality-dependent, magnetic field-independent MCD signals. It is speculated that the competitive effect between the spin alignment-induced and chirality-induced effective magnetic fields determines the energy splitting of opposite spins in the materials with different magnetisms.

Effect of Parecoxib Sodium on Myocardial Ischemia-Reperfusion Injury Rats.

BACKGROUND We aimed to explore the effect of parecoxib sodium on myocardial ischemia-reperfusion (I/R) injury rats and its mechanism. MATERIAL AND METHODS The coronary artery of Sprague-Dawley rats was occluded for 6 h of myocardial ischemia, followed by reperfusion for 30 min (I/R group). Before ischemia, parecoxib sodium (10 mg/kg) was intraperitoneally injected twice a day for 3 consecutive days, followed by reperfusion for 6 h (I/R+Pare group). The cardiac function and changes in the infarction area were evaluated via echocardiography in each group. The differences in the expressions of apoptosis-related proteins were determined via immunohistochemistry and western blotting. Then, the percentage of reactive oxygen species (ROS)⁺ cells and the content of lipid peroxide were detected, based on which the degree of oxidative stress was evaluated. Next, the expressions of nuclear factor-kappaB (NF-kappaB) and nuclear factor E2-related factor 2 (Nrf-2) signaling pathways and downstream target genes were determined using real-time quantitative polymerase chain reaction (PCR). RESULTS After treatment with parecoxib sodium, the cardiac function of I/R injury rats was restored, and the infarction area and apoptosis level were reduced (P<0.05). Parecoxib sodium reduced the levels of ROS and lipid peroxidation in myocardial I/R injury rats, thereby weakening oxidative stress. It also regulated the redox imbalance caused by I/R injury through regulating NF-kappaB and Nrf-2 (P<0.01). In addition, after treatment with parecoxib sodium, NF-kappaB was significantly downregulated, while Nrf-2 was upregulated, and the content of proinflammatory cytokines was obviously reduced (P<0.01). CONCLUSIONS Parecoxib sodium exerts a protective effect against myocardial I/R injury through regulating antioxidant and inflammatory mechanisms.

Resistance-Chiral Anisotropy of Chiral Mesostructured Half-metallic Fe3 O4 Films.

Half-metallic materials are theoretically predicted to be metallic and insulating, which have not been confirmed experimentally, and the predictions are still in doubt. We report the resistance-chiral anisotropy (R-ChA), i.e., chirality-dependent electrical conductivity, in chiral mesostructured Fe3 O4 films (CMFFs) grown on the substrates via a hydrothermal method using amino acids as symmetry-breaking agents. Two levels of chirality exist in the CMFFs: primary distortion of the crystal lattice forms twisted nanoflakes, and secondary helical stacking of nanoflakes forms fan-shaped nanoplates. At temperatures below 30 K, the CMFFs exhibited metallic conductivity and insulation for one handedness and the other, respectively. The chirality-dependent effective magnetic fields were speculated to stabilize the opposite spin in the antipodal chiral frame, which led to the free transport of electrons in one handedness of the chiral structure and immobility for the other handedness.

Chiral Mesostructured NiO Films with Spin Polarisation.

Spin polarisation is found in the centrosymmetric nonferromagnetic crystals, chiral mesostructured NiO films (CMNFs), fabricated through the symmetry-breaking effect of a chiral molecule. Two levels of chirality were identified: primary nanoflakes with atomically twisted crystal lattices and secondary helical stacking of the nanoflakes. Spin polarisation of the CMNFs was confirmed by chirality-dependent magnetic-tip conducting atomic force microscopy (mc-AFM) and magnetic field-independent magnetic circular dichroism (MCD). Electron transfer in the symmetry-breaking electric field was speculated to create chirality-dependent effective magnetic fields. The asymmetric spin-orbit coupling (SOC) generated by effective magnetic fields selectively modifies the opposite spin motion in the antipodal CMNFs. Our findings provide fundamental insights for directional spin control in unprecedented functional inorganic materials.

Chiral Mesostructured BiOBr Films with Circularly Polarized Colour Response.

Achieving strong and broadband circularly polarized colour responses in chiral inorganic materials is challenging. Here, we fabricated chiral mesostructured bismuth oxybromide (BiOBr) films (CMBFs) via hydrothermal growth using chiral sugar alcohols as symmetry-breaking agents. The layered slabs of BiOBr crystals with weak van-der-Waals interactions are prone to mismatching due to the chiral driving force, resulting in hierarchically chiral arrangements of fine size. Three levels of chirality exist in the CMBFs: primary, helical distortion crystal lattices of a nanoflake, secondary, helical stacking of nanoflakes to form nanoplates, and tertiary, chiral vortexes arranged by nanoplates. The CMBFs displayed optical activities (OAs) over a wide wavelength range of 350-2500 nm with an anisotropic factor of up to 0.99, which led to a significant chirality-dependent colour response to circularly polarized light. The high selectivity can be considered as the result of enhanced resonance due to structural-handedness matching and the synergistic effect of multiple OAs.

Enantiomeric Discrimination by Surface-Enhanced Raman Scattering-Chiral Anisotropy of Chiral Nanostructured Gold Films.

A surface-enhanced Raman scattering-chiral anisotropy (SERS-ChA) effect is reported that combines chiral discrimination and surface Raman scattering enhancement on chiral nanostructured Au films (CNAFs) equipped in the normal Raman scattering Spectrometer. The CNAFs provided remarkably higher enhancement factors of Raman scattering (EFs) for particular enantiomers, and the SERS intensity was proportional to the enantiomeric excesses (ee) values. Except for molecules with mesomeric species, all of the tested enantiomers exhibited high SERS-ChA asymmetry factors (g), ranging between 1.34 and 1.99 regardless of polarities, sizes, chromophores, concentrations and ee. The effect might be attributed to selective resonance coupling between the induced electric and magnetic dipoles associated with enantiomers and chiral plasmonic modes of CNAFs.

Silver Films with Hierarchical Chirality.

Physical fabrication of chiral metallic films usually results in singular or large-sized chirality, restricting the optical asymmetric responses to long electromagnetic wavelengths. The chiral molecule-induced formation of silver films prepared chemically on a copper substrate through a redox reaction is presented. Three levels of chirality were identified: primary twisted nanoflakes with atomic crystal lattices, secondary helical stacking of these nanoflakes to form nanoplates, and tertiary micrometer-sized circinates consisting of chiral arranged nanoplates. The chiral Ag films exhibited multiple plasmonic absorption- and scattering-based optical activities at UV/Vis wavelengths based on their hierarchical chirality. The Ag films showed chiral selectivity for amino acids in catalytic electrochemical reactions, which originated from their primary atomic crystal lattices.

Expression of Wnt3a, Wnt10b, ß-catenin and DKK1 in periodontium during orthodontic tooth movement in rats.

OBJECTIVE: To investigate the expression of Wnt3a, Wnt10b, ß-catenin and DKK1 in the periodontal ligament (PDL) during orthodontic tooth movement (OTM) in rats. MATERIALS AND METHODS: Nickel-titanium closed-coil springs were used to deliver an initial 50 g mesial force to the left maxillary first molars in 30 rats. The force was kept constant for 1, 3, 5, 7, 10 and 14 days until the animals were sacrificed. The right maxillary molars without force application served as control. Paraffin-embedded sections of the upper jaws were prepared for histological and immunohistochemical analyses to detect Wnt3a, Wnt10b, ß-catenin and DKK1 expression in PDL. RESULTS: Wnt3a, Wnt10b, ß-catenin and DKK1 were expressed on both the ipsilateral and contralateral sides of PDL in each group. After the application of orthodontic force, the expression of ß-catenin and DKK1 was initially increased and then decreased on both sides, with maximal levels of expression at day 7 and day 10, respectively. On the compression side, Wnt3a and Wnt10b levels started to increase at day 5, while on the tension side, these two molecules began to increase at day 1. Furthermore, the expression levels of Wnt3a, Wnt10b, and ß-catenin were much stronger on the tension side than on the compression side at any of the observation points, while DKK1 level was much higher on the compression side. CONCLUSION: Wnt3a, Wnt10b, ß-catenin and DKK1 expression may be related to the periodontal tissue remodeling following the application of an orthodontic force in rats. These observations suggest that the Wnt/ß-catenin signaling pathway may play a crucial role in periodontal tissue remodeling during OTM.

Hard-templating of chiral TiO2 nanofibres with electron transition-based optical activity.

The fabrication of optically active inorganic nanomaterials with chiral superstructures attracts attention because of their potential applications in chemical sensing and non-linear optics. Here, we present a facile way to prepare TiO2 nanofibres, in which the nanocrystals are helically arranged into a chiral superstructure. Notably, the chiral superstructure shows strong optical activity due to the difference of absorbing left- and right-handed circularly polarized light. This special optical activity resulted from electron transition from the valence band to the conduction band of TiO2 through a vicinal effect of helically arranged TiO2 nanocrystals.

Optically Active Nanostructured ZnO Films.

Inorganic nanomaterials endowed with hierarchical chirality could open new horizons in physical theory and applications because of their fascinating properties. Here, we report chiral ZnO films coated on quartz substrates with a hierarchical nanostructure ranging from atomic to micrometer scale. Three levels of hierarchical chirality exist in the ZnO films: helical ZnO crystalline structures that form primary helically coiled nanoplates, secondary helical stacking of these nanoplates, and tertiary nanoscale circinate aggregates formed by several stacked nanoplates. These films exhibited optical activity (OA) at 380 nm and in the range of 200-800 nm and created circularly polarized luminescence centered at 510 nm and Raman OA at 50-1400 cm(-1) , which was attributed to electronic transitions, scattering, photoluminescent emission, and Raman scattering in a dissymmetric electric field. The unprecedented strong OA could be attributed to multiple light scattering and absorption-enhanced light harvesting in the hierarchical structures.

Optically active chiral CuO "nanoflowers".

Helical symmetry can be found in most flowers with a rotation of contort petal aestivation. For micro- and nanoscale analogies, flower mimicking structures have been reproduced; however, the conceptual chirality of "nanoflowers" has not yet been defined. Here, the chirality of the "flower" was defined by its nanosized chiral structure and consequent optical activity (OA), opening new horizons for the physical theory and chiral materials. We report the surfactant-mediated hydrothermal synthesis of chiral CuO nanoflowers using sodium dodecyl sulfate (SDS) as a structure-directing agent, an amino alcohol as a symmetry-breaking agent, and cupric salt as the inorganic source. Two levels of hierarchical chirality exist for a CuO nanoflower including primary helically arranged "nanoflakes" and secondary helical "subnanopetals" that form "nanopetals". The nanoflowers exhibited a prominent optical response to circularly polarized light (CPL) at the absorption bands characteristic of CuO.

Spatial diversity processing mechanism based on the distributed underwater acoustic communication system.

To address the problem of unreliable single-link underwater acoustic communication caused by large signal delays and strong multipath effects in shallow water environments, this paper proposes a distributed underwater acoustic diversity communication system (DUA-DCS). DUA-DCS employs a maneuverable distributed cross-medium buoy network to form multiple distributed, non-coherent, and parallel communication links. In the uplink, a receiving diversity processing mechanism of joint decision feedback equalizer embedded phase-locked loop and maximum signal-to-interference ratio combining (DFE-PLL-MSIRC) is proposed to achieve waveform-level diversity combining of underwater signals. A phase-locked loop module is embedded in each branch of the decision feedback equalizer to eliminate the residual frequency and phase errors after Doppler compensation. Meanwhile, the combining coefficients are determined based on the maximum signal-to-interference ratio criterion, taking into account the residual inter-symbol interference after equalization, resulting in efficient and accurate computation. Additionally, the combined decision values are fed back to the feedback filters in each branch to ensure more accurate feedback output. Simulation and lake experiment results demonstrate that, compared to the single-link communication system, DFE-PLL-MSIRC can achieve a diversity gain of more than 5.2 dB and obtain about 3 dB more diversity gain than the comparison algorithm. And the BER of DFE-PLL-MSIRC can be reduced by at least one order of magnitude, which is lower by at least 0.6 order of magnitude compared to the comparison algorithm. In the downlink, a transmitting diversity processing mechanism of complex orthogonal space-time block coding (COSTBC) is proposed. By utilizing a newly designed generalized complex orthogonal transmission matrix, complete transmission diversity can be achieved at the coding rate of 3/4. Compared to the single-link communication system, the system can achieve a diversity gain of more than 6 dB.

Chirality-Induced Memristor of Chiral Nanostructured Half-Metallic Fe3O4 Films.

Spintronic memristors, which combine the nonvolatile characteristics of memristors with the scalability of a spin-transfer torque device, are expected to play a crucial role in advancing quantitative information processing. This field commonly relies on magnetic tunnel junctions, domain wall motion, and spin waves. Here, the discovery of chirality-induced memristor behavior in chiral nanostructured Fe3O4 films (CNFFs) is reported. These CNFFs are grown on fluorine tin oxide (FTO) substrates using enantiomeric glutamic acid (Glu) as symmetry-breaking agents and consist of arrays of oriented twisted nanofibers. At 100 K, the L-CNFF exhibits memristor behavior as a pinched hysteresis loop in the I-V curve, while the D-CNFF exhibits semiconductor behavior with constant electrical resistance. The intrinsic spin polarization of half-metallic Fe3O4 and the chirality-induced spin selectivity (CISS) are speculated to contribute to the memristor in one handedness of the chiral structure. These findings present a novel spinristor that combines the functions of a memristor and a spin-filter based on chiral structures, which may promote the development of spintronic devices.

The pleiotropic enhancer enh9 promotes cell proliferation and migration in non-small cell lung cancer via ERMP1 and PD-L1.

Enhancers, cis-acting DNA elements for transcriptional regulation, are important regulators of cell identity and disease. However, of the hundreds of thousands of enhancers annotated in the human genome, only a few have been studied for their regulatory mechanisms and functions in cancer progression and therapeutic resistance. Here, we report the pleiotropy of one enhancer (named enh9) in both cell proliferation and migration in non-small cell lung cancer (NSCLC) cells. By integrating multi-genomic data, ERMP1 and PD-L1 were screened out as potential targets of enh9. CUT&Tag sequencing demonstrated that enh9 was involved in the genomic interactions between the transcription factor RELA and the promoters of ERMP1 and PD-L1. In addition, ERMP1 and PD-L1 were validated to be involved in cell proliferation and migration, respectively. Our study fully elucidated the function and transcriptional regulation mechanisms of enh9 in NSCLC. The exploration on enhancers is promising to provide new insights for cancer diagnosis and therapy.

Genome-wide analysis of bZIP transcription factors and their expression patterns in response to methyl jasmonate and low-temperature stresses in Platycodon grandiflorus.

Background: Platycodon grandiflorus belongs to the genus Platycodon and has many pharmacological effects, such as expectorant, antitussive, and anti-tumor properties. Among transcription factor families peculiar to eukaryotes, the basic leucine zipper (bZIP) family is one of the most important, which exists widely in plants and participates in many biological processes, such as plant growth, development, and stress responses. However, genomic analysis of the bZIP gene family and related stress response genes has not yet been reported in P. grandiflorus. Methods: P. grandiflorus bZIP (PgbZIP) genes were first identified here, and the phylogenetic relationships and conserved motifs in the PgbZIPs were also performed. Meanwhile, gene structures, conserved domains, and the possible protein subcellular localizations of these PgbZIPs were characterized. Most importantly, the cis-regulatory elements and expression patterns of selected genes exposed to two different stresses were analyzed to provide further information on PgbZIPs potential biological roles in P. grandiflorus upon exposure to environmental stresses. Conclusions: Forty-six PgbZIPs were identified in P. grandiflorus and divided into nine groups, as displayed in the phylogenetic tree. The results of the chromosomal location and the collinearity analysis showed that forty-six PgbZIP genes were distributed on eight chromosomes, with one tandem duplication event and eleven segmental duplication events identified. Most PgbZIPs in the same phylogenetic group have similar conserved motifs, domains, and gene structures. There are cis-regulatory elements related to the methyl jasmonate (MeJA) response, low-temperature response, abscisic acid response, auxin response, and gibberellin response. Ten PgbZIP genes were selected to study their expression patterns upon exposure to low-temperature and MeJA treatments, and all ten genes responded to these stresses. The real-time quantitative polymerase chain reaction (RT-qPCR) results suggest that the expression levels of most PgbZIPs decreased significantly within 6 h and then gradually increased to normal or above normal levels over the 90 h following MeJA treatment. The expression levels of all PgbZIPs were significantly reduced after 3 h of the low-temperature treatment. These results reveal the characteristics of the PgbZIP family genes and provide valuable information for improving P. grandiflorus's ability to cope with environmental stresses during growth and development.

Water-dependent optical activity inversion of chiral DNA-silica assemblies.

Chirality is widely found in nature and is expressed hierarchically in many organic-inorganic hybrid materials. Optical activity (OA) is the most fundamental attribute of these chiral materials. In this study, we found that the OA of impeller-like chiral DNA-silica assemblies (CDSAs) was inverted with the addition of water. The state of DNA under dry and wet conditions, and the dual chirality of chiral DNA layers and twisted helical arrays of opposite handedness in CDSAs were considered to exert predominant effects on the OAs. The circular dichroism (CD) responses for the dry CDSAs were mostly attributed to the chiral arrangement of DNA layers, whereas the opposite CD responses for the wet CDSAs primarily originated from twisted helical arrays of DNA molecules. The observed CD signals were a super-position of the two opposing OA responses. The increase in the longitudinal relation of DNA molecules due to the recovery of a double-helical structure of DNA in the presence of water was considered to be the reason for the increase in intensity of the CD signals that originated from the twisted helical array, which led to the inversion of OA of the CDSAs. The inversion of the plasmon-resonance-based OAs for the chiral-arranged achiral Ag nanoparticles (NPs) located in the channels of the CDSAs in dry and wet states further confirmed the dual chirality of DNA packing. Such research on DNA assemblies and metal NPs with dual, opposite chirality assists in the understanding of DNA hierarchical chirality in living systems and the creation of macroscopic ordered helical materials and biosensors.

Chiral mesostructured NiFe2O4 films with chirality induced spin selectivity.

Chiral mesostructured NiFe2O4 films (CMNFFs) were synthesized using L-/D-tyrosine as symmetry-breaking and structure-directing agents through a hydrothermal method. For the first time, chirality induced spin selectivity was directly observed in these ferrimagnetic materials using chirality-dependent magnetic-tip conducting atomic force microscopy (mc-AFM).