Endoplasmic reticulum targeted fluorescent probe for real-time monitoring the viscosity changes induced by calcium homeostasis disruption.

The endoplasmic reticulum (ER) acts as the major storage site for calcium ions, which are messenger ions for intracellular signaling. Disruption of calcium ion homeostasis can significantly affect the viscosity, polarity and pH of the ER. However, it is still unclear the relationship between the viscosity changes in ER and the imbalance of calcium ion homeostasis. Herein, we developed a novel fluorescent probe, named TPA, for monitoring viscosity changes that specifically targets the endoplasmic reticulum rather than mitochondria or lysosomes. TPA probe displayed good stability, as well as high responsiveness and selectivity to viscosity. The fluorescence intensity of TPA was significantly enhanced with the increased concentration or incubation time of the stimulating agents(i.e., tunicamycin), showing high responsiveness to the viscosity changes in ER. Furthermore, the TPA probe successfully demonstrated that an increase in intracellular calcium ion concentration leads to an increase in ER viscosity, whereas a decrease in calcium ion concentration leads to a decrease viscosity in ER. Both in vitro and in vivo experiments demonstrated that TPA probe successfully detected the viscosity changes in ER, especially the effects of calcium ion homeostasis disruption on ER. Overall, the TPA probe represents an efficient method for studying the relationship between calcium ion homeostasis and ER viscosity.

Monitoring the Mitochondrial Viscosity Changes During Cuproptosis with Iridium(III) Complex Probe via In Situ Phosphorescence Lifetime Imaging.

Cuproptosis is a novel copper-dependent form of programmed cell death, displaying important regulatory functions in many human diseases, including cancer. However, the relationship between the changes in mitochondrial viscosity, a key factor associated with cellular malfunction, and cuproptosis is still unclear. Herein, we prepared a phosphorescent iridium (Ir) complex probe for precisely monitoring the changes of mitochondrial viscosity during cuprotosis via phosphorescence lifetime imaging. The Ir complex probe possessed microsecond lifetimes (up to 1 µs), which could be easily distinguished from cellular autofluorescence to improve the imaging contrast and sensitivity. Benefiting from the long phosphorescence lifetime, excellent viscosity selectivity, and mitochondrial targeting abilities, the Ir complex probe could monitor the increase in the mitochondrial viscosity during cuproptosis (from 46.8 to 68.9 cP) in a quantitative manner. Moreover, through in situ fluorescence imaging, the Ir complex probe successfully monitored the increase in viscosity in zebrafish treated with lipopolysaccharides or elescolomol-Cu2+, which were well-known cuproptosis inducers. We anticipate that this new Ir complex probe will be a useful tool for in-depth understanding of the biological effects of mitochondrial viscosity during cuproptosis.

A "turn-on" red cyclometalated iridium (III) complex for long-term tracking the diffusion of CORM-2 in cells and zebrafish.

Transition metal carbonyl compound of CO releasing molecules (CORMs) are widely used to treat arthritis, tumor and immune. They play a physiological role by directly acting on target tissues to release CO for disease treatment without matrix metabolism after dissolution. It is important to track the level and diffusion process of CORMs in vivo to control CO dose and distribution, facilitating to understand the roles of CORMs in disease treatment. Herein, we designed two red ring Ir1/2 complexes with a large stokes shift. Both Ir1 and Ir2 complexes probes can sensitively and selectively respond to CORM-2. The probe Ir1 exhibits rapid reaction with CORM-2 in Phosphate Buffered Saline within 1 min, showing a detection limitation of 0.13 µM and manifesting a linear relationship with the CORM-2 concentration from 0 to 70 µM at λem = 618 nm. Due to low toxicity even after 12 h exposure and fluorescence stability, this probe has been successfully used for continuous tracking the diffusion process of CORM-2 in living cells for up to 60 min and visualizing CORM-2 distribution in zebrafish. Additionally, this probe showed a good capacity for deep penetration (126 µm), suggesting the potential in detecting CORM-2 in living tissues.

Boric acid group-functional ruthenium complex as a novel fluorescence probe for robust detection of propyl gallate and tert-butyl hydroquinone by tuning the pH.

This study reported a ruthenium complex-based fluorescence probe, achieving rapid and sequential detection of propyl gallate (PG) and tert-butyl hydroquinone (TBHQ) for the first time by tuning pH only. Under 480 nm excitation, probe exhibited intensive emission at 620 nm, which was selectively quenched by PG at pH 7.0 due to the covalent binding between the boric acid of probe and o-diphenol hydroxyl of PG. Then pH was tuned to 7.4, the emission was significantly quenched by TBHQ because of the π-π stacking between aromatic rings of probe and paraquinone of TBHQ. This probe realized specific and sensitive detection of PG and TBHQ with wide range and low detection limit (0.26 µM for PG and 0.66 µM for TBHQ). Furthermore, a portable visual test paper detection platform was built based on this probe for rapid and sensitive detection of antioxidants in food, which was of great significance for market regulation.

Combination of colorimetry, inner filter effect-induced fluorometry and smartphone­based digital image analysis: A versatile and reliable strategy for multi-mode visualization of food dyes.

Herein, a multi-mode visualization platform was initiated for in-situ detection of food dyes (FDs) by combining colorimetry, fluorometry and smartphone­based digital image analysis, in which water-dispersible quantum dots (QDs) were served as nanoprobes. Colorimetry was achieved by color comparison, while both fluorometry and fluorescence quantification were performed through inner filter effect (IFE)-induced fluorescence quenching, then color information (RGB & gray-scale values) of colorimetry and fluorometry was picked by a smartphone to reconstruct digitized alignments. Since IFE mechanism was concentration-dependent but did not rely on the interaction between fluorophore and quencher, the whole process of fluorescence response could be finished within 10 s, and both color gradients and fluorescence changes showed fine mappings to FDs concentrations in the range of 1.0 × 10-3∼0.035 mg/mL for brilliant blue, and 1.0 × 10-4∼0.1 mg/mL for Allura red and sunset yellow. As a proof-of-concept, the in-situ multi-mode visualization of these FDs in real beverages was experimentally proved to be highly feasible and reliable as compared with instrumental techniques like UV-vis/fluorescence spectrometry, along with HPLC. Finally, this strategy was extended to the multi-mode visualization of non-food dyes in three simulated wastewater samples with high credibility by contrast with the true additive amounts of model dyes.

Comparative analysis of chloroplast genomes of endangered heterostylous species Primula wilsonii and its closely related species.

Primula, well known for its heterostyly, is the largest genus in the family Primulaceae with more than 500 species. The considerable species number has introduced a huge challenge for taxonomy. The phylogenetic relationships among Primula still maintain unresolved due to frequent hybridization and introgression between closely related species. In this study, we sequenced and assembled the complete chloroplast genomes of Primula wilsonii Dunn, which is a PSESP (plant species with extremely small populations), using Illumina sequencing and compared its genomic sequences with those of four related Primula species. The chloroplast genomes of Primula species were similar in the basic structure, gene order, and GC content. The detected 38 SSRs (simple sequence repeats) loci and 17 hypervariable regions had many similarities in P. wilsonii, P. anisodora, P. miyabeana, and P. poissonii, but showed a significant difference compared with those in P. secundiflora. Slight variations were observed among Primula chloroplast genomes, in consideration of the relatively stable patterns of IR (inverted repeats) contraction and expansion. Phylogenetic analysis based on chloroplast genomes and protein-coding genes confirmed three major clades in Chinese Primula, but the infrageneric sections were not in accordance with morphological traits. The P. poissonii complex was confirmed here and P. anisodora was the most closely related species to P. wilsonii. Overall, the chloroplast genome sequences provided useful genetic and evolutionary information for phylogeny and population genetics on Chinese Primula species.

Water-responsive 4D printing based on self-assembly of hydrophobic protein "Zein" for the control of degradation rate and drug release.

Four-dimensional (4D) printing is a promising technology that provides solutions for compelling needs in various fields. Most of the reported 4D printed systems are based on the temporal shape transformation of printed subjects. Induction of temporal heterogenicity in functions in addition to shape may extend the scope of 4D printing. Herein, we report a 4D printing approach using plant protein (zein) gel inspired by the amyloid fibrils formation mechanism. The printing of zein gel in a specialized layered-Carbopol supporting bath with different water concentrations in an ethanol-water mixture modulates hydrophobic and hydrogen bonding that causes temporal changes in functions. The part of the construct printed in a supporting bath with higher water content exhibits higher drug loading, faster drug release and degradation than those printed in the supporting bath with lower water content. Tri-segment conduit and butterfly-shaped construct with two asymmetrical wings are printed using this system to evaluate biomedical function as nerve conduit and drug delivery system. 4D printed conduits are also effective as a drug-eluting urethral stent in the porcine model. Overall, this study extends the concept of 4D printing beyond shape transformation and presents an approach of fabricating specialized baths for 4D printing that can also be extended to other materials to obtain 4D printed medical devices with translational potential.

A platinum-ruthenium hybrid prodrug with multi-enzymatic activities for chemo-catalytic therapy of hypoxic tumors.

Regulation of tumor hypoxia and redox homeostasis is a promising strategy for cancer therapy. Nanocatalytic medicine has played more and more important roles in this field because it can cleverly convert the efficiency and selectivity of catalysis into high therapeutic efficiency. Herein, we developed a platinum(iv)-ruthenium hybrid prodrug, named as Pt-Ru, for efficient chemo-catalytic synergistic therapy of hypoxic tumors. The ruthenium hybridization endowed the Pt(iv) prodrug with multi-enzyme catalytic activity, that is, mimicking catalase (CAT) to generate O2 in situ, mimicking peroxidase (POD) to produce reactive oxygen species, and mimicking glutathione peroxidase (GPx) to deplete GSH, thus effectively overcoming tumor hypoxia and cisplatin resistance. As a result, Pt-Ru treatment led to a superior anticancer efficacy to cisplatin both in vitro and in vivo. This work suggested redox homeostasis regulation as a tantalizing angle for developing the next generation of platinum drugs.

[Expression, purification and bioactivity analysis of a recombinant fusion protein rHSA-hFGF21 in Pichia pastoris].

Human fibroblast growth factor 21 (hFGF21) has become a candidate drug for regulating blood glucose and lipid metabolism. The poor stability and short half-life of hFGF21 resulted in low target tissue availability, which hampers its clinical application. In this study, the hFGF21 was fused with a recombinant human serum albumin (HSA), and the resulted fusion protein rHSA-hFGF21 was expressed in Pichia pastoris. After codon optimization, the recombinant gene fragment rHSA-hFGF21 was inserted into two different vectors (pPIC9k and pPICZαA) and transformed into three different strains (X33, GS115 and SMD1168), respectively. We investigated the rHSA-hFGF21 expression levels in three different strains and screened an engineered strain X33-pPIC9K-rHSA-hFGF21 with the highest expression level. To improve the production efficiency of rHSA-hFGF21, we optimized the shake flask fermentation conditions, such as the OD value, methanol concentration and induction time. After purification by hollow fiber membrane separation, Blue affinity chromatography and Q ion exchange chromatography, the purity of the rHSA-hFGF21 protein obtained was 98.18%. Compared to hFGF21, the biostabilities of rHSA-hFGF21, including their resistance to temperature and trypsinization were significantly enhanced, and its plasma half-life was extended by about 27.6 times. Moreover, the fusion protein rHSA-hFGF21 at medium and high concentration showed a better ability to promote glucose uptake after 24 h of stimulation in vitro. In vivo animal studies showed that rHSA-hFGF21 exhibited a better long-term hypoglycemic effect than hFGF21 in type 2 diabetic mice. Our results demonstrated a small-scale production of rHSA-hFGF21, which is important for large-scale production and clinical application in the future.

Mechanism of Depression through Brain Function Imaging of Depression Patients and Normal People.

In recent years, functional magnetic resonance technology has discovered that abnormal connections in different brain regions of the brain may serve as the pathophysiological mechanism of mental illness. Exploring the mechanism of information flow and integration between different brain regions is of great significance for understanding the pathophysiological mechanism of mental illness. This article aims to analyze the mechanism of depression by comparing human brain images of normal people and patients with depression and conduct research. Fluoxetine, a selective 5-HT reuptake inhibitor (SSRI) widely used in clinical practice, can selectively inhibit 5-HT transporter and block the reuptake of 5-HT by the presynaptic membrane. The effect of 5-HT is prolonged and increased, thereby producing antidepressant effects. It has low affinity for adrenergic, histaminergic, and cholinergic receptors and has a weaker effect, resulting in fewer adverse reactions. This paper uses the comparative experiment method and the Welch method and uses the average shortest path length L to describe the average value of the shortest path length between two nodes in the network. Attention refers to the ability of a person's mental activity to point and to concentrate on something. Sustained attention means that attention is kept on a certain cognitive object or activity for a certain period of time, which is also called the stability of attention. The research on attention of depression patients generally focuses on continuous attention, and the results obtained show inconsistencies. Most studies have shown that the sustained attention of the depression group is significantly worse than that of the healthy control group. An overview of magnetic resonance imaging technology and an analysis of depression based on resting state were carried out. The key brain areas of the sample core network were scanned, and the ALFF results were analyzed. The data showed that the severity of depression in the depression group was negatively correlated with the ReHo value in the posterior left cerebellum (P=0.010). The sense of despair was negatively correlated with the ReHo value in the posterior right cerebellum (P=0.013). The diurnal variation was negatively correlated with the ReHo value of the left ring (P=0.014). It was positively correlated with the ReHo value of the left ventricle (P=0.048). This experiment has better completed the research on the mechanism of depression by analyzing the functional images of patients with depression and normal human brain.

Toxicity of CuS/CdS semiconductor nanocomposites to liver cells and mice liver.

Semiconductor nanomaterials not only bring great convenience to peoples lives but also become a potential hazard to human health. The purpose of this study was to evaluate the toxicity of CuS/CdS nanocomposites in hepatocytes and mice liver. The CuS/CdS semiconductor nanocomposites were synthesized by a biomimetic synthesis - ion exchange strategy. Nanosize was confirmed by high-resolution transmission electron microscopy and dynamic light scattering. The composition and physical properties were measured by powder X-ray diffraction, Fourier transform infrared spectra, atomic absorption spectroscopy, thermogravimetry-differential scanning calorimetry and zeta potential analysis. The results revealed that CuS/CdS nanocomposites had 8.7 nm diameter and negative potential. Ion exchange time could adjust the ratio of CuS and CdS in nanocomposites. The toxicological study revealed that CuS/CdS nanocomposites could be internalized into liver cells, inhibited endogenous defense system (e.g. GSH and SOD), induced the accumulation of oxidation products (e.g. ROS, GSSG and MDA), and caused hepatocyte apoptosis. The in vivo experiments in Balb/c mice showed that the experimental dose (4 mg/kg) didn't cause observable changes in mice behavior, physical activity and pathological characteristics, but the continuous accumulation of Cd2+ in the liver and kidney might be responsible for its long-term toxicity.

The complete plastome of Primula wilsonii, a heterostylous ornamental species.

Primula wilsonii Dunn is a perennial herb in section Proliferae Pax of Primula L. with small population sizes in the field. Here, we constructed the complete plastome of the P. wilsonii using Illumina sequencing technology. The circular plastome was 151,677 bp in size, and comprises a large single-copy (LSC) region of 83,510 bp, a small single-copy (SSC) region of 17,765 bp, and a pair of inverted repeats (IR) of 25,201 bp. The GC content was 36.99% overall, with 34.89%, 30.18%, and 42.87% for the LSC, SSC, and IR regions, respectively. The plastome comprised 130 unique genes including 84 protein-coding genes, 37 tRNAs, and 8 rRNAs. The ML phylogenetic analysis based on 17 plastomes in Primulaceae showed a strong sister relationship with P. anisodora in section Proliferae.

Intracellular Paclitaxel Delivery Facilitated by a Dual-Functional CPP with a Hydrophobic Hairpin Tail.

In our pervious study, a dual-functional peptide R7 was developed to form a complex with paclitaxel (PTX) for enhancement of PTX translocation. However, because of the unstable noncovalent bond between R7 and PTX, PTX redistributed after the introduction of heparin, leading to R7-PTX complex dissociation, further causing less PTX penetration than expected. Thus, a novel positive CPP carrier of P9 was developed to improve CPP-PTX affinity via a double-proline (Pro, P) hairpin tail and enhance PTX translocation through the reduction of translocation energy barrier, confirmed by the MM-PBSA analysis and umbrella sampling simulation. Cellular uptake study reveals that P9 can quickly translocate into the HeLa cells within 1 min and exhibits no noticeable cytotoxicity. Compared to R7, P9 is able to help PTX translocation, leading to a remarkable increase in the intracellular concentration of PTX, eventually resulting in a significant loss in tumor cell viability. In vivo experiments demonstrate that a vein injection of P9-PTX complex dramatically inhibits tumor growth. Our study provides a novel perspective for designing CPP-facilitated drug carrier to enhance antitumor efficiency.

Regulating Tumor N6 -Methyladenosine Methylation Landscape using Hypoxia-Modulating OsSx Nanoparticles.

The epigenetic dysregulation and hypoxia are two important factors that drive tumor malignancy, and N6 -methyladenosine (m6 A) in mRNA is involved in the regulation of gene expression. Herein, a nanocatalyst OsSx -PEG (PEG = poly(ethylene glycol)) nanoparticles (NPs) as O2 modulator is developed to improve tumor hypoxia. OsSx -PEG NPs can significantly downregulate genes involved in hypoxia pathway. Interestingly, OsSx -PEG NPs elevate RNA m6 A methylation levels to cause the m6 A-dependent mRNA degradation of the hypoxia-related genes. Moreover, OsSx -PEG NPs can regulate the expression of RNA m6 A methyltransferases and demethylases. Finally, DOX@OsSx -PEG (DOX = doxorubicin; utilized as a model drug) NPs modulate tumor hypoxia and regulate mRNA m6 A methylation of hypoxia-related genes in vivo. As the first report about relationship between catalytic nanomaterials and RNA modifications, the research opens a new avenue for unveiling the underlying action mechanisms of hypoxia-modulating nanomaterials and shows potential of regulating RNA modification to overcome chemoresistance.

LncRNA LEF1-AS1 promotes metastasis of prostatic carcinoma via the Wnt/ß-catenin pathway.

BACKGROUND: Long noncoding RNAs (lncRNAs) are important functional regulators of many biological processes of cancers. However, the mechanisms by which lncRNAs modulate androgen-independent prostate cancer (AIPC) development remain largely unknown. METHODS: Next-generation sequencing technology and RT-qPCR were used to assess LEF1-AS1 expression level in AIPC tissues and adjacent normal tissues. Functional in vitro experiments, including colony formation, EDU and transwell assays were performed to assess the role of LEF1-AS1 in AIPC. Xenograft assays were conducted to assess the effect of LEF1-AS1 on cell proliferation in vivo. Chromatin immunoprecipitation (ChIP) and RNA binding protein immunoprecipitation (RIP) assays were performed to elucidate the regulatory network of LEF1-AS1. RESULTS: The next-generation sequencing results showed that LEF1-AS1 is significantly overexpressed in AIPC. Furthermore, our RT-qPCR assay data showed that LEF1-AS1 is overexpressed in AIPC tissues. Functional experiments showed that LEF1-AS1 promotes the proliferation, migration, invasion and angiogenic ability of AIPC cells in vitro and tumour growth in vivo by recruiting the transcription factor C-myb to the promoter of FZD2, inducing its transcription. Furthermore, LEF1-AS1 was shown to function as a competing endogenous RNA (ceRNA) that sponges miR-328 to activate CD44. CONCLUSION: In summary, the results of our present study revealed that LEF1-AS1 acts as a tumour promoter in the progression of AIPC. Furthermore, the results revealed that LEF1-AS1 functions as a ceRNA and regulates Wnt/ß-catenin pathway activity via FZD2 and CD44. Our results provide new insights into the mechanism that links the function of LEF1-AS1 with AIPC and suggests that LEF1-AS1 may serve as a novel potential target for the improvement of AIPC therapy.

Precisely Assembled Nanoparticles against Cisplatin Resistance via Cancer-Specific Targeting of Mitochondria and Imaging-Guided Chemo-Photothermal Therapy.

Cisplatin resistance in tumor cells is known mainly due to the reduced accumulation of platinum ions by efflux, detoxification by intracellular GSH, and nucleotide excision repair machinery-mediated nuclear DNA repair. In this work, theranostic Pt(IV)-NPs, which are precisely self-assembled by biotin-labeled Pt(IV) prodrug derivative and cyclodextrin-functionalized IR780 in a 1:1 molecular ratio, have been developed for addressing all these hurdles via mitochondria-targeted chemotherapy solely or chemophotothermal therapy. In these nanoparticles, IR780 as a small-molecule dye acts as a mitochondria-targeting ligand to make Pt(IV)-NPs relocate finally in the mitochondria and release cisplatin. As demonstrated by in vitro and in vivo experiments, Pt(IV)-NPs can markedly facilitate cancer-specific mitochondrial targeting, inducing mitochondrial dysfunction and mitochondrial DNA (mtDNA) damage, thus greatly increasing the Pt accumulation, reducing the GSH levels, and avoiding DNA repair machinery in cisplatin-resistant cancer cells (A549R), finally resulting in significant inhibition of A549R tumor growth on animal models by chemotherapy solely. Upon near-infrared irradiation, mitochondria-targeted chemophotothermal synergistic therapy can be realized, further overcoming cisplatin resistance and even eliminating A549R tumors completely. Moreover, such novel Pt(IV)-NPs integrate multimodal targeting (cancer and mitochondria targeting), imaging (near-infrared imaging and photoacoustic imaging), and therapeutic (chemo- and photothermal therapy) moieties in a constant ratio (1:1:1) into a single, reproducible, and structurally homogeneous entity, avoiding nonuniform drug loading and premature leakage as well as the discrete steps of imaging and therapy, which thus is more beneficial for precise therapeutics and future clinical translation.

Nos2 deficiency enhances carbon tetrachloride-induced liver injury in aged mice.

OBJECTIVES: As a multifunctional molecule, NO has different effects on liver injury. The present work aimed to investigate the effects of Nos2 knockout (KO) on acute liver injury in aged mice treated with carbon tetrachloride (CCl4). MATERIALS AND METHODS: The acute liver injury model was produced by CCl4 at 10 ml/kg body weight in 24-month-old Nos2 KO mice and wild type (WT) mice groups. The histological changes, transaminase and glutathione (GSH) contents, and the expressions of liver function genes superoxide dismutase (SOD2) and butyrylcholinesterase (BCHE), as well as apoptosis- and inflammation-associated genes were detected at 0, 6, 16, 20, 28, and 48 hr, respectively. RESULTS: Compared with WT aged mice, there are more fat droplets in liver tissues of Nos2 KO aged mice, and the serum levels of ALT and AST were elevated in the KO group; in addition, there was a decrease in the expression of SOD2 and BCHE and GSH content at multiple time-points. Furthermore, the expression of apoptosis protein CASPASE-3 was elevated from 20 to 48 hr, the same as CASPASE-9 at 28 and 48 hr and pro-apoptotic protein BAX at 6 and 28 hr, while the expression of apoptosis inhibitory protein BCL2 declined at 6 and 28 hr; at the same time the mRNA expressions of genes related to inflammation were increased at different extents in liver extracts of Nos2 KO aged mice. CONCLUSION: Nos2 KO exacerbated liver injury probably by elevated oxidative stress, apoptosis and inflammation response in CCl4-induced aged mice liver intoxication model.

CAIXplatins: Highly Potent Platinum(IV) Prodrugs Selective Against Carbonic Anhydrase†IX for the Treatment of Hypoxic Tumors.

Hypoxia and the acidic microenvironment play a vital role in tumor metastasis and angiogenesis, generally compromising the chemotherapeutic efficacy. This provides a tantalizing angle for the design of platinum(IV) prodrugs for the effective and selective killing of solid tumors. Herein, two carbonic anhydrase IX (CAIX)-targeting platinum(IV) prodrugs have been developed, named as CAIXplatins. Based on their strong affinity for and inhibition of CAIX, CAIXplatins can not only overcome hypoxia and the acidic microenvironment, but also inhibit metabolic pathways of hypoxic cancer cells, resulting in a significantly enhanced therapeutic effect on hypoxic MDA-MB-231 tumors both in vitro and in vivo compared with cisplatin/oxaliplatin, accompanied with excellent anti-metastasis and anti-angiogenesis activities. Furthermore, the cancer selectivity indexes of CAIXplatins are 70-90 times higher than those of cisplatin/oxaliplatin with effectively alleviated side-effects.

A rare case of scrotal angiolipoma and the literature review.

Angiolipoma has been reported in many cases, which often occurring subcutaneously in the trunk and limbs. However, angiolipoma rarely occurs in the scrotum. In order to better understand its biological characteristics, clinical features and prognosis, in this case, a 41-year-old male with painful angiolipoma in the scrotum was reported.

ZNF143 in Chromatin Looping and Gene Regulation.

ZNF143, a human homolog of the transcriptional activator Staf, is a C2H2-type protein consisting of seven zinc finger domains. As a transcription factor (TF), ZNF143 is sequence specifically binding to chromatin and activates the expression of protein-coding and non-coding genes on a genome scale. Although it is ubiquitous expressed, its expression in cancer cells and tissues is usually higher than that in normal cells and tissues. Therefore, abnormal expression of ZNF143 is related to cancer cell survival, proliferation, differentiation, migration, and invasion, suggesting that new small molecules can be designed by targeting ZNF143 as it may be a good potential biomarker and therapeutic target for related cancers. However, the mechanism on how ZNF143 regulates its targeting gene remains unclear. Recently, with the development of chromatin conformation capture (3C) and its derivatives, and high-throughput sequencing technology, new findings have been obtained in the study of ZNF143. Pioneering studies have showed that ZNF143 binds directly to promoters and contributes to chromatin interactions connecting promoters to distal regulatory elements, such as enhancers. Further, it has proved that ZNF143 is involved in CCCTC-binding factor (CTCF) in establishing the conserved chromatin loops by cooperating with cohesin and other partners. These results indicate that ZNF143 is a key loop formation factor. In addition, we report ZNF143 is dynamically bound to chromatin during the cell cycle demonstrated that it is a potential mitotic bookmarking factor. It may be associated with CTCF for mitosis-to-G1 phase transition and chromatin loop re-establishment in early G1 phase. In the future, researchers could further clarify the fine mechanism of ZNF143 in mediating chromatin loops with the help of CUT&RUN (CUT&Tag) and Cut-C technology. Thus, in this review, we summarize the research progress of TF ZNF143 in detail and also predict the potential functions of ZNF143 in cell fate and identity based on our recent discoveries.