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Graphical abstract, Highlights • The hierarchical levels of TAD boundaries were tissue- and cell type-specific. • The TAD nesting level of genes in tumors is different from that in normal tissue. • Hierarchical TAD level of genes is related to abnormal transcription and prognosis 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.

Graphical abstract, Small cell lung cancer (SCLC) is an aggressive form of lung cancer that uniquely changes the chromosomal structure, although the basis of aberrant gene expression in SCLC remains largely unclear. Topologically associated domains (TADs) are structural and functional units of the human genome. Genetic and epigenetic alterations in the cancer genome can lead to the disruption of TAD boundaries and may cause gene dysregulation. To understand the potential regulatory role of this process in SCLC, we developed the TAD boundary alteration–related gene identification in tumors (TARGET) computational framework, which enables the systematic identification of candidate dysregulated genes associated with altered TAD boundaries. Using TARGET to compare gene expression profiles between SCLC and normal human lung fibroblast cell lines, we identified >100 genes in this category, of which 24 were further verified in samples from patients with SCLC using NanoString. The analysis revealed synergistic chromatin structure alteration at the A/B compartment and TAD boundary levels that underlies aberrant gene expression in SCLC. TARGET is a novel and powerful tool that can be used to explore the relationship of chromatin structure alteration to gene dysregulation related to SCLC tumorigenesis, progression, and prognosis.

Adenosine (A) to inosine (I) RNA editing is the most prevalent RNA editing mechanism in humans and plays critical roles in tumorigenesis. However, the effects of radiation on RNA editing were poorly understood, and a deeper understanding of the radiation-induced cancer is imperative. Here, we analyzed BEP2D (a human bronchial epithelial cell line) and radiation-induced malignantly transformed cell lines with next generation sequencing. By performing an integrated analysis of A-to-I RNA editing, we found that single-nucleotide variants (SNVs) might induce the downregulation of ADAR2 enzymes, and further caused the abnormal occurrence of RNA editing in malignantly transformed cell lines. These editing events were significantly enriched in differentially expressed genes between normal cell line and malignantly transformed cell lines. In addition, oncogenes CTNNB1 and FN1 were highly edited and significantly overexpressed in malignantly transformed cell lines, thus may be responsible for the lung cancer progression. Our work provides a systematic analysis of RNA editing from cell lines derived from human bronchial epithelial cells with high-throughput RNA sequencing and DNA sequencing. Moreover, these results provide further evidence for RNA editing as an important tumorigenesis mechanism.

Adenosine (A) to inosine (I) RNA editing is the most prevalent RNA editing mechanism in humans and play critical roles in tumorigenesis. However, the effects of radiation on RNA editing and the mechanisms of radiation-induced cancer were poorly understood. Here, we analyzed human bronchial epithelial BEP2D cells and radiation-induced malignantly transformed cells with next generation sequencing. By performing an integrated analysis of A-to-I RNA editing, we found that genome-encoded single-nucleotide polymorphisms (SNPs) might induce the downregulation of ADAR2 enzymes, and further caused the abnormal occurrence of RNA editing in malignantly transformed cells. These editing events were significantly enriched in differentially expressed genes between normal cells and cancer cells. In addition, oncogenes CTNNB1 and FN1 were highly edited and significantly overexpressed in cancer cells, thus may be responsible for the lung cancer progression. Our work provides a systematic analysis of RNA editing from lung tumor specimens with high-throughput RNA sequencing and DNA sequencing. Moreover, these results demonstrate further evidence for RNA editing as an important tumorigenesis mechanism.

Essential genes are those whose functions govern critical processes that sustain life in the organism. Recent gene-editing technologies have provided new opportunities to characterize essential genes. Here, we present an integrated analysis for comprehensively and systematically elucidating the genetic and regulatory characteristics of human essential genes. First, essential genes act as “hubs” in protein-protein interactions networks, in chromatin structure, and in epigenetic modifications, thus are essential for cell growth. Second, essential genes represent the conserved biological processes across species although gene essentiality changes itself. Third, essential genes are import for cell development due to its discriminate transcription activity in both embryo development and oncogenesis. In addition, we develop an interactive web server, the Human Essential Genes Interactive Analysis Platform (HEGIAP) (http://sysomics.com/HEGIAP/), which integrates abundant analytical tools to give a global, multidimensional interpretation of gene essentiality. Our study provides a new view for understanding human essential genes.

Advances in genome-wide association studies (GWAS) and large-scale sequencing studies have resulted in an impressive and growing list of disease- and trait-associated genetic variants. Most studies have emphasised the discovery of genetic variation in coding sequences, however, the noncoding regulatory effects responsible for human disease and cancer biology have been substantially understudied. To better characterise the cis-regulatory effects of noncoding variation, we performed a comprehensive analysis of the genetic variants in HOT (high-occupancy target) regions, which are considered to be one of the most intriguing findings of recent large-scale sequencing studies. We observed that GWAS variants that map to HOT regions undergo a substantial net decrease and illustrate development-specific localisation during haematopoiesis. Additionally, genetic risk variants are disproportionally enriched in HOT regions compared with LOT (low-occupancy target) regions in both disease-relevant and cancer cells. Importantly, this enrichment is biased toward disease- or cancer-specific cell types. Furthermore, we observed that cancer cells generally acquire cancer-specific HOT regions at oncogenes through diverse mechanisms of cancer pathogenesis. Collectively, our findings demonstrate the key roles of HOT regions in human disease and cancer and represent a critical step toward further understanding disease biology, diagnosis and therapy.

In this work, metabonomic methods utilizing (1)H NMR spectroscopy and multivariate statistical technique have been applied to investigate the metabolic profiles of SAM. The serum metabolome of senescence-prone 8 (SAMP8), a murine model of age-related learning and memory deficits and Alzheimer's disease (AD), was compared with that of control, senescence-resistant 1 (SAMR1), which shows normal aging process. Serum samples were collected for study from both male and female 12-month-old SAMP8 and age matched SAMR1 ( n = 5). (1)H NMR spectra of serum were analyzed by pattern recognition using principal components analysis. The results showed that the serum metabolic patterns of SAMP8 and SAMR1 were significantly different due to strains and genders. Subtle differences in the endogenous metabolite profiles in serum between SAMP8 and SAMR1 were observed. The most important metabolite responsible for the strain separation was lack of inosine, which meant the protective function of anti-inflammation, immunomodulation and neuroprotection might be attenuated in SAMP8. Other differential metabolites observed between strains included decreased glucose, PUFA, choline, phosphocholine, HDL, LDL, D-3-hydoxybutyrate, citrate and pyruvate and increased lactate, SFA, alanine, methionine, glutamine and VLDL in serum of SAMP8 compared with those of SAMR1, suggesting perturbed glucose and lipid metabolisms in SAMP8. Besides the differences observed between the strains, an impact of gender on metabolism was also found. The females exhibited larger metabolic deviations than males and these gender differences in SAMP8 were much larger than in SAMR1. Higher levels of VLDL, lactate and amino acids and lower levels of HDL, LDL and unsaturated lipids were detected in female than in male SAMP8. These facts indicated that the metabolism disequilibrium in female and male SAMP8 was different and this may partly explain that females were more prone to AD than males. The results of this work may provide valuable clues to the understanding of the mechanisms of the senile impairment and the pathological changes of AD, as well as show the potential power of the combination of the NMR technique and the pattern recognition method for the analysis of the biochemical changes of certain pathophysiologic conditions.