Computational methods for the prediction of chromatin interaction and organization using sequence and epigenomic profiles.

The exploration of three-dimensional chromatin interaction and organization provides insight into mechanisms underlying gene regulation, cell differentiation and disease development. Advances in chromosome conformation capture technologies, such as high-throughput chromosome conformation capture (Hi-C) and chromatin interaction analysis by paired-end tag (ChIA-PET), have enabled the exploration of chromatin interaction and organization. However, high-resolution Hi-C and ChIA-PET data are only available for a limited number of cell lines, and their acquisition is costly, time consuming, laborious and affected by theoretical limitations. Increasing evidence shows that DNA sequence and epigenomic features are informative predictors of regulatory interaction and chromatin architecture. Based on these features, numerous computational methods have been developed for the prediction of chromatin interaction and organization, whereas they are not extensively applied in biomedical study. A systematical study to summarize and evaluate such methods is still needed to facilitate their application. Here, we summarize 48 computational methods for the prediction of chromatin interaction and organization using sequence and epigenomic profiles, categorize them and compare their performance. Besides, we provide a comprehensive guideline for the selection of suitable methods to predict chromatin interaction and organization based on available data and biological question of interest.

Spatial density of open chromatin: an effective metric for the functional characterization of topologically associated domains.

Topologically associated domains (TADs) are spatial and functional units of metazoan chromatin structure. Interpretation of the interplay between regulatory factors and chromatin structure within TADs is crucial to understand the spatial and temporal regulation of gene expression. However, a computational metric for the sensitive characterization of TAD regulatory landscape is lacking. Here, we present the spatial density of open chromatin (SDOC) metric as a quantitative measurement of intra-TAD chromatin state and structure. SDOC sensitively reflects epigenetic properties and gene transcriptional activity in TADs. During mouse T-cell development, we found that TADs with decreased SDOC are enriched in repressed developmental genes, and the joint effect of SDOC-decreasing and TAD clustering corresponds to the highest level of gene repression. In addition, we revealed a pervasive preference for TADs with similar SDOC to interact with each other, which may reflect the principle of chromatin organization.

Characterization of Gut Microbiota, Bile Acid Metabolism, and Cytokines in Intrahepatic Cholangiocarcinoma.

Intrahepatic cholangiocarcinoma (ICC), a type of bile duct cancer, has a high mortality rate. Gut microbiota, bile acid (BA) metabolism, and cytokines have not been characterized in patients with ICC, and better noninvasive diagnostic approaches for ICC are essential to be established. Therefore, in this study we aimed to improve our understanding of changes in gut microbiota, BA metabolism, and cytokines in patients with ICC. We found that the α-diversities and ß-diversities of ICC were highest and that the abundances of four genera (Lactobacillus, Actinomyces, Peptostreptococcaceae, and Alloscardovia) were increased in patients with ICC compared with those in patients with hepatocellular carcinoma or liver cirrhosis and in healthy individuals. The glycoursodeoxycholic acid and tauroursodeoxycholic acid (TUDCA) plasma-stool ratios were obviously increased in patients with ICC. Furthermore, the genera Lactobacillus and Alloscardovia that were positively correlated with TUDCA plasma-stool ratios were combined to discriminate ICC from the other three diseases. Vascular invasion (VI) frequently led to a poor prognosis in patients with ICC. Compared with patients with ICC without VI, patients with VI had a greater abundance of the family Ruminococcaceae, increased levels of plasma interleukin (IL)-4 and six conjugated BAs, and decreased levels of plasma IL-6 and chenodeoxycholic acid. A positive correlation between plasma taurocholic acid and IL-4 was observed in patients with ICC. Plasma TUDCA was negatively correlated with the abundance of the genus Pseudoramibacter and the survival time of patients with ICC, but had no effect on tumor size, as determined in two murine tumor models. Conclusion: In this study, we identified some biomarkers, including gut microbiota, BAs and inflammatory cytokines, for the diagnosis of ICC and prediction of VI in patients with ICC.

DeepHiC: A generative adversarial network for enhancing Hi-C data resolution.

Hi-C is commonly used to study three-dimensional genome organization. However, due to the high sequencing cost and technical constraints, the resolution of most Hi-C datasets is coarse, resulting in a loss of information and biological interpretability. Here we develop DeepHiC, a generative adversarial network, to predict high-resolution Hi-C contact maps from low-coverage sequencing data. We demonstrated that DeepHiC is capable of reproducing high-resolution Hi-C data from as few as 1% downsampled reads. Empowered by adversarial training, our method can restore fine-grained details similar to those in high-resolution Hi-C matrices, boosting accuracy in chromatin loops identification and TADs detection, and outperforms the state-of-the-art methods in accuracy of prediction. Finally, application of DeepHiC to Hi-C data on mouse embryonic development can facilitate chromatin loop detection. We develop a web-based tool (DeepHiC, http://sysomics.com/deephic) that allows researchers to enhance their own Hi-C data with just a few clicks.

Thermal transport and spin-dependent Seebeck effect in parallel step-like zigzag graphene nanoribbon junctions.

By using nonequilibrium molecular dynamics, thermal transport through a series of parallel step-like graphene nanoribbon (GNR) junctions is investigated. The theoretical results show that the thermal current flows preferentially from wide GNRs to narrow ones, displaying a pronounced thermal rectification effect. Moreover, several step-like GNR-based devices are designed, and the thermally driven spin-dependent currents are calculated by using density functional theory combined with the nonequilibrium Green's function approach. We find that thermal spin-dependent currents with opposite flow directions are generated when a temperature gradient is applied along the GNRs, indicating the occurrence of a spin-dependent Seebeck effect (SDSE). More interestingly, a negative differential SDSE occurs in the thermal spin currents, and the odd and even law appears in the spin-dependent currents, thermopowers and thermoelectric conversion efficiencies. Our theoretical results indicate that the parallel step-like GNRs are potential candidates to design spin caloritronics devices hosting thermal rectification and multiple thermal-spin transport functionalities.

The accessible promoter-mediated supplementary effect of host factors provides new insight into the tropism of SARS-CoV-2.

In the past year, the rapid spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) resulted in the worldwide coronavirus disease 2019 (COVID-19) pandemic. Yet our understanding of the SARS-CoV-2 tropism mechanism is still insufficient. In this study, we examined the chromatin accessibility at the promoters of host factor genes (ACE2, TMPRSS2, NRP1, BSG, CTSL, and FURIN) in 14 tissue types, 23 tumor types, and 189 cell lines. We showed that the promoters of ACE2 and TMPRSS2 were accessible in a tissue- and cell-specific pattern, which is accordant with previous clinical research on SARS-CoV-2 tropism. We were able to further verify that type I interferon (IFN) could induce angiotensin-converting enzyme 2 (ACE2) expression in Caco-2 cells by enhancing the binding of HNF1A, the transcription factor of ACE2, to ACE2 promoter without changing chromatin accessibility. We then performed transcription factor (TF)-gene interactions network and pathway analyses and discovered that the TFs regulating host factor genes are enriched in pathways associated with viral infection. Finally, we established a novel model that suggests that open chromatin at the promoter mediates the host factors' supplementary effect and ensures SARS-CoV-2 entry. Our work uncovers the relationship between epigenetic regulation and SARS-CoV-2 tropism and provides clues for further investigation of COVID-19 pathogenesis.

Regulatory patterns analysis of transcription factor binding site clustered regions and identification of key genes in endometrial cancer.

Endometrial cancer (EC) is one of the three fatal tumors of the female reproductive system. Epigenetic alterations have been reported to be important in tumorigenesis, especially the chromatin accessibility changes and transcription factor binding differences. However, the regulatory mechanism underlying epigenetic alterations in EC development remains unclear. Here, we identified and characterized transcription factor binding site clustered regions (TFCRs) by integrating chromatin accessibility and transcription factor binding information. We totally identified 78,820 TFCRs and explored the relationship between TFCRs and regulatory elements, gene expression and mutation. Finally, we constructed a bioinformatic framework to identify candidate oncogenes and screened 13 candidate key genes, which may serve as potential diagnostic markers or therapeutic targets of EC.

The hierarchical folding dynamics of topologically associating domains are closely related to transcriptional abnormalities in cancers.

Recent studies have shown that the three-dimensional (3D) structure of chromatin is associated with cancer progression. However, the roles of the 3D genome structure and its dynamics in cancer remains largely unknown. In this study, we investigated hierarchical topologically associating domain (TAD) structures in cancers and defined a "TAD hierarchical score (TH score)" for genes, which allowed us to assess the TAD nesting level of all genes in a simplified way. We demonstrated that the TAD nesting levels of genes in a tumor differ from those in normal tissue. Furthermore, the hierarchical TAD level dynamics were related to transcriptional changes in cancer, and some of the genes in which the hierarchical level was altered were significantly related to the prognosis of cancer patients. Overall, the results of this study suggest that the folding dynamics of TADs are closely related to transcriptional abnormalities in cancers, emphasizing that the function of hierarchical chromatin organization goes beyond simple chromatin packaging efficiency.

One-dimensional transition metal dihalide nanowires as robust bipolar magnetic semiconductors.

One-dimensional (1D) materials with robust ferromagnetic ground states are difficult to achieve but provide a significant platform for potential spintronic device applications in future. Herein, a new family of 1D transition metal dihalide (TMCl2; where TM = Cu, Co, Cr) nanowires are proposed by using first-principles calculations. Their dynamic stability is ensured by Born-Oppenheimer molecular dynamics simulations. The electronic structures demonstrate that both CoCl2 and CuCl2 nanowires are promising bipolar magnetic semiconductors (BMSs) and can be converted into 1D half-metal materials by a small amount of carrier doping. The CrCl2 nanowire is an antiferromagnetic semiconductor (AFS). The formation of a BMS is attributed to the superexchange coupling between the Co/Cu atoms through the 3p orbitals in the Cl atoms. By using Monte Carlo simulations, we found that the CoCl2 nanowire has a Curie point of 6 K, while the CuCl2 nanowire has a corresponding Curie point of 14 K. Our results allow us to put forward a strategy to realize 1D BMSs and to design low-dimensional AF spintronic devices.

Targeting Src family kinase member Fyn by Saracatinib attenuated liver fibrosis in vitro and in vivo.

Recent studies suggest that Src family kinase (SFK) plays important roles in systemic sclerosis and pulmonary fibrosis. However, how SFKs contributed to the pathogenesis of liver fibrosis remains largely unknown. Here, we investigated the role of Fyn, a member of SFK, in hepatic stellate cell (HSC) activation and liver fibrosis, and evaluated the anti-fibrotic effects of Saracatinib, a clinically proven safe Fyn inhibitor. Fyn activation was examined in human normal and fibrotic liver tissues. The roles of Fyn in HSC activation and liver fibrosis were evaluated in HSC cell lines by using Fyn siRNA and in Fyn knockout mice. The effects of Saracatinib on HSC activation and liver fibrosis were determined in primary HSCs and CCl4 induced liver fibrosis model. We showed that the Fyn was activated in the liver of human fibrosis patients. TGF-ß induced the activation of Fyn in HSC cell lines. Knockdown of Fyn significantly blocked HSC activation, proliferation, and migration. Fyn deficient mice were resistant to CCl4 induced liver fibrosis. Saracatinib treatment abolished the activation of Fyn, downregulated the Fyn/FAK/N-WASP signaling in HSCs, and subsequently prevented the activation of HSCs. Saracatinib treatment significantly reduced the severity liver fibrosis induced by CCl4 in mice. In conclusions, our findings supported the critical role of Fyn in HSC activation and development of liver fibrosis. Fyn could serve as a promising drug target for liver fibrosis treatment. Fyn inhibitor Saracatinib significantly inhibited HSC activation and attenuated liver fibrosis in mouse model.

A Novel NHERF1 Mutation in Human Breast Cancer and Effects on Malignant Progression.

Na+/H+ exchanger regulatory factor 1 (NHERF1) has been reported to interact with post-synaptic density protein/Drosophila disc large tumour suppressor/zonula occludens 1 protein (PDZ) binding proteins by its two PDZ domains. These associations have effects on cellular signal transductions. NHERF1 has also been indicated as a cancer-related gene in several solid tumour types. We identified a novel mutation (A190D), of the PDZ2 domain of NHERF1 in breast cancer tissues. NHERF1 A190D mutation abolished NHERF1 modulation of proliferation and migration. In this study, we found that NHERF1 A190D mutation increased nuclear localisation of the protein compared to wild-type NHERF1. It has been reported that YES-associated protein (YAP) interacts with NHERF1. Here we found that NHERF1 A190D mutation increased the binding affinity between NHERF1 and YAP, which inhibited the phosphorylation of YAP. These data suggest that wild-type NHERF1 acts as a tumour suppressor, while NHERF1 A190D mutation abolishes the tumour-suppressive effect in cancer cells, due to A190D mutation-mediated nuclear NHERF1 translocation and induction of YAP phosphorylation.

Reduced NOV expression correlates with disease progression in colorectal cancer and is associated with survival, invasion and chemoresistance of cancer cells.

Aberrant expression of nephroblastoma overexpressed (NOV) has been evident in certain malignancies. In the current study, we aim to investigate the role played by NOV in colorectal cancer (CRC). NOV expression was determined in a cohort of 359 CRC tissues and 174 normal colorectal tissues. Its impact on CRC cells was investigated using in vitro NOV knockdown and overexpression models. NOV transcripts were reduced in the CRC tumours compared with the paired adjacent normal colorectal tissues (p < 0.01) and was associated with distant metastases. NOV knockdown resulted in increased cell proliferation and invasion of RKO cells, whilst an opposite effect was seen in the HT115 NOV over expressing cells. A positive association between Caspase-3/-8 and NOV was seen in NOV knockdown and overexpression cell lines which contributed to the survival of serum deprived CRC cells. Further investigation showed that NOV regulated proliferation, survival and invasion through the JNK pathway. NOV knockdown in RKO cells reduced the responsiveness to 5-Fluorouracil treatment, whilst overexpression in HT115 cells exhibited a contrasting effect. Taken together, NOV is reduced in CRC tumours and this is associated with disease progression. NOV inhibits the proliferation and invasion of CRC cells in vitro. Inhibition of proliferation is mediated by a regulation of Caspase-3/-8, via the JNK pathway, which has potential for predicting and preventing chemoresistance.

A Novel NHERF1 Mutation in Human Breast Cancer Inactivates Inhibition by NHERF1 Protein in EGFR Signaling.

BACKGROUND: Na(+)/H(+) exchanger regulatory factor 1 (NHERF1) has been reported to interact with many cancer-related proteins. We recently identified a novel NHERF1 mutation (E43G) in breast tumours. MATERIALS AND METHODS: The candidates of NHERF1 mutation were identified in breast cancer tissues by polymerase chain reaction and DNA sequencing. Wild-type NHERF1 and E43G mutation were expressed in NHERF1-knockdown cells (MCF7ΔNHERF1) and low-NHERF1-expressing cells (SKMES-1). The effects of mutated NHERF1 on cell functions were examined using in vitro methods. Glutathione S-transferase pull-down assays and western blotting were performed to study the effects of NHERF1 mutation on its interaction with cancer-related proteins. RESULTS: Compared to wild-type NHERF1, expression of the mutated NHERF1 failed to suppress malignant traits in cancer cells, attenuated interaction of NHERF1 protein with epidermal growth factor receptor (EGFR), and inactivated its inhibition of EGF-induced Akt and extracellular regulated protein kinases (ERK) activation. CONCLUSION: The results show the causal role of NHERF1 in the regulation of the EGFR pathway and the progression of breast cancer.

ADAM29 Expression in Human Breast Cancer and its Effects on Breast Cancer Cells In Vitro.

BACKGROUND: A Disintegrin and Metalloprotease Domain 29 (ADAM29) is involved in many important physiological processes. Recent studies have demonstrated that ADAM29 is a susceptibility locus showing traits as a risk factor for breast cancer under genome-wide significance, however, the clinical relevance and cellular function of ADAM29 in breast cancer have not been reported. MATERIALS AND METHODS: In this study, we assessed the expression levels of ADAM29 in a cohort of human breast cancer specimens. We also used MDA-MB-231 cells with differing ADAM29 expression and assessed the influence of ADAM29 and its mutations on the MDA-MB-231 cell line. RESULTS: Increased transcript expression of ADAM29 was observed in breast cancer tissues compared to normal ones. The expression of ADAM29 and its mutations in different domains significantly influenced proliferation, migration and invasion of breast cancer cells in vitro. CONCLUSION: ADAM29 may represent a prognostic factor in human breast cancer, as well as a novel molecular candidate to be used as a therapeutic target.

The cellular distribution of Na+/H+ exchanger regulatory factor 1 is determined by the PDZ-I domain and regulates the malignant progression of breast cancer.

The oncogenic role of ectopic expression of Na+/H+ exchanger regulatory factor 1 (NHERF1) was recently suggested. Here, we show that NHERF1 was upregulated in high grades compared with low grades. Increased NHERF1 expression was correlated with poor prognosis and poor survival. NHERF1 expression was higher in the nucleus of cancer cells than in contiguous non- mammary epithelial cells. A novel mutation, namely NHERF1 Y24S, was identified in human breast cancer tissues and shown to correspond to a conserved residue in the PDZ-I domain of NHERF1. Truncation and mutation of the PDZ-I domain of NHERF1 increased the nuclear distribution of the NHERF1 protein, and this redistribution was associated with the malignant phenotype of breast cancer cells, including growth, migration, and adhesion. The present results suggest a role for NHERF1 in the progression of breast cancer mediated by the nuclear distribution of the NHERF1 protein, as determined by the truncation or key site mutation of the PDZ-I domain.