Mitogenome evidence shows two radiation events and dispersals of matrilineal ancestry from northern coastal China to the Americas and Japan.

Although it is widely recognized that the ancestors of Native Americans (NAs) primarily came from Siberia, the link between mitochondrial DNA (mtDNA) lineage D4h3a (typical of NAs) and D4h3b (found so far only in East China and Thailand) raises the possibility that the ancestral sources for early NAs were more variegated than hypothesized. Here, we analyze 216 contemporary (including 106 newly sequenced) D4h mitogenomes and 39 previously reported ancient D4h data. The results reveal two radiation events of D4h in northern coastal China, one during the Last Glacial Maximum and the other within the last deglaciation, which facilitated the dispersals of D4h sub-branches to different areas including the Americas and the Japanese archipelago. The coastal distributions of the NA (D4h3a) and Japanese lineages (D4h1a and D4h2), in combination with the Paleolithic archaeological similarities among Northern China, the Americas, and Japan, lend support to the coastal dispersal scenario of early NAs.

Metabolic Modeling Identifies a Novel Molecular Type of Glioblastoma Associated with Good Prognosis.

Glioblastoma (GBM) is one of the most aggressive forms of cancer. Although IDH1 mutation indicates a good prognosis and a potential target for treatment, most GBMs are IDH1 wild-type. Identifying additional molecular markers would help to generate personalized therapies and improve patient outcomes. Here, we used our recently developed metabolic modeling method (genome-wide precision metabolic modeling, GPMM) to investigate the metabolic profiles of GBM, aiming to identify additional novel molecular markers for this disease. We systematically analyzed the metabolic reaction profiles of 149 GBM samples lacking IDH1 mutation. Forty-eight reactions showing significant association with prognosis were identified. Further analysis indicated that the purine recycling, nucleotide interconversion, and folate metabolism pathways were the most robust modules related to prognosis. Considering the three pathways, we then identified the most significant GBM type for a better prognosis, namely N+P-. This type presented high nucleotide interconversion (N+) and low purine recycling (P-). N+P--type exhibited a significantly better outcome (log-rank p = 4.7 × 10-7) than that of N-P+. GBM patients with the N+P--type had a median survival time of 19.6 months and lived 65% longer than other GBM patients. Our results highlighted a novel molecular type of GBM, which showed relatively high frequency (26%) in GBM patients lacking the IDH1 mutation, and therefore exhibits potential in GBM prognostic assessment and personalized therapy.

The landscape of aging.

Aging is characterized by a progressive deterioration of physiological integrity, leading to impaired functional ability and ultimately increased susceptibility to death. It is a major risk factor for chronic human diseases, including cardiovascular disease, diabetes, neurological degeneration, and cancer. Therefore, the growing emphasis on "healthy aging" raises a series of important questions in life and social sciences. In recent years, there has been unprecedented progress in aging research, particularly the discovery that the rate of aging is at least partly controlled by evolutionarily conserved genetic pathways and biological processes. In an attempt to bring full-fledged understanding to both the aging process and age-associated diseases, we review the descriptive, conceptual, and interventive aspects of the landscape of aging composed of a number of layers at the cellular, tissue, organ, organ system, and organismal levels.

Mechanism of Thymus Rejuvenation in Elderly Macaques.

Senile thymus atrophy is an important factor leading to decreased immune function. Repairing the atrophic thymus tissue structure, rebuilding immune function, and replenishing the number of exogenous stem cells may be ideal methods. In this study, bone marrow mesenchymal stem cells were intravenously infused into elderly macaques. We found that thymus volume was substantially increased, some thymus tissue regeneration was observed, the degree of thymus tissue fibrosis decreased, collagen fiber deposition decreased, cortical and medulla structures emerged gradually, the number of apoptotic cells decreased significantly, and the expression of apoptosis-related proteins decreased. For the effects of stem cell therapy on aging-related genes, we performed transcriptomic analysis of thymus tissue. The results show the expression pattern of the tissue transcriptome tended to be similar to the thymus expression pattern in young macaques compared with the elderly group, reverse aging-related proteins. Based on the results, it is suggested that stem cell therapy is an ideal method to prevent or reverse the aging of the thymus.

ETS1 acts as a regulator of human healthy aging via decreasing ribosomal activity.

Adaptation to reduced energy production during aging is a fundamental issue for maintaining healthspan or prolonging life span. Currently, however, the underlying mechanism in long-lived people remains poorly understood. Here, we analyzed transcriptomes of 185 long-lived individuals (LLIs) and 86 spouses of their children from two independent Chinese longevity cohorts and found that the ribosome pathway was significantly down-regulated in LLIs. We found that the down-regulation is likely controlled by ETS1 (ETS proto-oncogene 1), a transcription factor down-regulated in LLIs and positively coexpressed with most ribosomal protein genes (RPGs). Functional assays showed that ETS1 can bind to RPG promoters, while ETS1 knockdown reduces RPG expression and alleviates cellular senescence in human dermal fibroblast (HDF) and embryonic lung fibroblast (IMR-90) cells. As protein synthesis/turnover in ribosomes is an energy-intensive cellular process, the decline in ribosomal biogenesis governed by ETS1 in certain female LLIs may serve as an alternative mechanism to achieve energy-saving and healthy aging.

System-level metabolic modeling facilitates unveiling metabolic signature in exceptional longevity.

Although it is well known that metabolic control plays a crucial role in regulating the health span and life span of various organisms, little is known for the systems metabolic profile of centenarians, the paradigm of human healthy aging and longevity. Meanwhile, how to well characterize the system-level metabolic states in an organism of interest remains to be a major challenge in systems metabolism research. To address this challenge and better understand the metabolic mechanisms of healthy aging, we developed a method of genome-wide precision metabolic modeling (GPMM) which is able to quantitatively integrate transcriptome, proteome and kinetome data in predictive modeling of metabolic networks. Benchmarking analysis showed that GPMM successfully characterized metabolic reprogramming in the NCI-60 cancer cell lines; it dramatically improved the performance of the modeling with an R2 of 0.86 between the predicted and experimental measurements over the performance of existing methods. Using this approach, we examined the metabolic networks of a Chinese centenarian cohort and identified the elevated fatty acid oxidation (FAO) as the most significant metabolic feature in these long-lived individuals. Evidence from serum metabolomics supports this observation. Given that FAO declines with normal aging and is impaired in many age-related diseases, our study suggests that the elevated FAO has potential to be a novel signature of healthy aging of humans.

A pair of long intergenic non-coding RNA LINC00887 variants act antagonistically to control Carbonic Anhydrase IX transcription upon hypoxia in tongue squamous carcinoma progression.

BACKGROUND: Long noncoding RNAs (lncRNAs) are important regulators in tumor progression. However, their biological functions and underlying mechanisms in hypoxia adaptation remain largely unclear. RESULTS: Here, we established a correlation between a Chr3q29-derived lncRNA gene and tongue squamous carcinoma (TSCC) by genome-wide analyses. Using RACE, we determined that two novel variants of this lncRNA gene are generated in TSCC, namely LINC00887_TSCC_short (887S) and LINC00887_TSCC_long (887L). RNA-sequencing in 887S or 887L loss-of-function cells identified their common downstream target as Carbonic Anhydrase IX (CA9), a gene known to be upregulated by hypoxia during tumor progression. Mechanistically, our results showed that the hypoxia-augmented 887S and constitutively expressed 887L functioned in opposite directions on tumor progression through the common target CA9. Upon normoxia, 887S and 887L interacted. Upon hypoxia, the two variants were separated. Each RNA recognized and bound to their responsive DNA cis-acting elements on CA9 promoter: 887L activated CA9's transcription through recruiting HIF1α, while 887S suppressed CA9 through DNMT1-mediated DNA methylation. CONCLUSIONS: We provided hypoxia-permitted functions of two antagonistic lncRNA variants to fine control the hypoxia adaptation through CA9.

Comparative analysis of long noncoding RNAs in long-lived mammals provides insights into natural cancer-resistance.

Mouse and rats are staple model organisms that have been traditionally used for oncological studies; however, their short lifespan and highly prone to cancers limit their utilizationsin understanding the mechanisms of cancer resistance. In recent years, several studies of the non-standard long-lived mammalian species like naked mole rat (NMR) have provided new insights of mechanisms in natural anti-cancer. How long-lived species genetically maintain longevity and cancer-resistance remains largely elusive. To better understand the underlying anti-cancer mechanisms in long-lived mammals, we genome widely identified long noncoding RNA (lncRNA) transcripts of two longevous mammals, bowhead whale (BW, Balaena mysticetus) and Brandt's bat (BB, Myotis brandtii) and featured their sequence traits, expression patterns, and their correlations with cancer-resistance. Similar with naked mole rat (NMR, Heterocephalus glaber), the most long-lived rodent, BW and BB lncRNAs show low sequence conservation and dynamic expressions among tissues and physiological stages. By utilizing k-mers clustering, 75-136 of BW, BB and NMR lncRNAs were found in close relation (Pearson's r ≥0.9, p < 0.01) with human ageing diseases related lncRNAs (HAR-Lncs). In addition, we observed thousands of BB and BW lncRNAs strongly co-expressed (r > 0.8 or r <-0.8, p < 0.01) with potential tumour suppressors, indicating that lncRNAs are potentially involved in anti-cancer regulation in long-lived mammals. Our study provides the basis for lncRNA researches in perspectives of evolution and anti-cancer studies. Abbreviations: BW: bowhead whale; BB: Brandt's bat; NMR: naked mole rat; LLM: long-lived mammal; HTS: human tumour-suppressors; PTS: potential tumour suppressor; ARD: ageing related diseases; HAR-Lncs: lncRNAs that related with human ageing diseases; Kmer-lncs: lncRNAs in long-lived mammal species that corelated (Pearson'sr ≥0.9, p < 0.01) with the 10 HAR-Lncs by k-mers clustering; All-lncs: all the lncRNAs in long-lived mammal species; SDE-lncs: significant differentially expressed lncRNAs.

Glycerophosphodiester phosphodiesterase 1 (GDE1) acts as a potential tumor suppressor and is a novel therapeutic target for non-mucin-producing colon adenocarcinoma.

Colon adenocarcinoma (COAD) represents a major public health issue due to its high incidence and mortality. As different histological subtypes of COAD are related to various survival outcomes and different therapies, finding specific targets and treatments for different subtypes is one of the major demands of individual disease therapy. Interestingly, as these different subtypes show distinct metabolic profiles, it may be possible to find specific targets related to histological typing by targeting COAD metabolism. In this study, the differential expression patterns of metabolism-related genes between COAD (n = 289) and adjacent normal tissue (n = 41) were analyzed by one-way ANOVA. We then used weighted gene co-expression network analysis (WGCNA) to further identify metabolism-related gene connections. To determine the critical genes related to COAD metabolism, we obtained 2,114 significantly differentially expressed genes (DEGs) and 12 modules. Among them, we found the hub module to be significantly associated with histological typing, including non-mucin-producing colon adenocarcinoma and mucin-producing colon adenocarcinoma. Combining survival analysis, we identified glycerophosphodiester phosphodiesterase 1 (GDE1) as the most significant gene associated with histological typing and prognosis. This gene displayed significantly lower expression in COAD compared with normal tissues and was significantly correlated with the prognosis of non-mucin-producing colon adenocarcinoma (p = 0.0017). Taken together, our study showed that GDE1 exhibits considerable potential as a novel therapeutic target for non-mucin-producing colon adenocarcinoma.

TICRR Contributes to Tumorigenesis Through Accelerating DNA Replication in Cancers.

DNA replication is precisely regulated in cells and its dysregulation can trigger tumorigenesis. Here we identified that the TOPBP1 interacting checkpoint and replication regulator (TICRR) mRNA level was universally and highly expressed in 15 solid cancer types. Depletion of TICRR significantly inhibited tumor cell growth, colony formation and migration in vitro, and strikingly inhibited tumor growth in the xenograft model. We reveal that knockdown of TICRR inhibited not only the initiation but also the fork progression of DNA replication. Suppression of DNA synthesis by TICRR silencing caused DNA damage accumulation, subsequently activated the ATM/CHK2 dependent p53 signaling, and finally induced cell cycle arrest and apoptosis at least in p53-wild cancer cells. Further, we show that a higher TICRR level was associated with poorer overall survival (OS) and disease free survival (DFS) in multiple cancer types. In conclusion, our study shows that TICRR is involved in tumorigenesis by regulating DNA replication, acting as a common biomarker for cancer prognosis and could be a promising target for drug-development and cancer treatment.

Identification of four hub genes associated with adrenocortical carcinoma progression by WGCNA.

BACKGROUND: Adrenocortical carcinoma (ACC) is a rare and aggressive malignant cancer in the adrenal cortex with poor prognosis. Though previous research has attempted to elucidate the progression of ACC, its molecular mechanism remains poorly understood. METHODS: Gene transcripts per million (TPM) data were downloaded from the UCSC Xena database, which included ACC (The Cancer Genome Atlas, n = 77) and normal samples (Genotype Tissue Expression, n = 128). We used weighted gene co-expression network analysis to identify gene connections. Overall survival (OS) was determined using the univariate Cox model. A protein-protein interaction (PPI) network was constructed by the search tool for the retrieval of interacting genes. RESULTS: To determine the critical genes involved in ACC progression, we obtained 2,953 significantly differentially expressed genes and nine modules. Among them, the blue module demonstrated significant correlation with the "Stage" of ACC. Enrichment analysis revealed that genes in the blue module were mainly enriched in cell division, cell cycle, and DNA replication. Combined with the PPI and co-expression networks, we identified four hub genes (i.e., TOP2A, TTK, CHEK1, and CENPA) that were highly expressed in ACC and negatively correlated with OS. Thus, these identified genes may play important roles in the progression of ACC and serve as potential biomarkers for future diagnosis.

Transcriptome evidence reveals enhanced autophagy-lysosomal function in centenarians.

Centenarians (CENs) are excellent subjects to study the mechanisms of human longevity and healthy aging. Here, we analyzed the transcriptomes of 76 centenarians, 54 centenarian-children, and 41 spouses of centenarian-children by RNA sequencing and found that, among the significantly differentially expressed genes (SDEGs) exhibited by CENs, the autophagy-lysosomal pathway is significantly up-regulated. Overexpression of several genes from this pathway, CTSB, ATP6V0C, ATG4D, and WIPI1, could promote autophagy and delay senescence in cultured IMR-90 cells, while overexpression of the Drosophila homolog of WIPI1, Atg18a, extended the life span in transgenic flies. Interestingly, the enhanced autophagy-lysosomal activity could be partially passed on to their offspring, as manifested by their higher levels of both autophagy-encoding genes and serum beclin 1 (BECN1). In light of the normal age-related decline of autophagy-lysosomal functions, these findings provide a compelling explanation for achieving longevity in, at least, female CENs, given the gender bias in our collected samples, and suggest that the enhanced waste-cleaning activity via autophagy may serve as a conserved mechanism to prolong the life span from Drosophila to humans.

Accelerated DNA methylation changes in middle-aged men define sexual dimorphism in human lifespans.

BACKGROUND: Accelerated age-associated DNA methylation changes in males may explain the earlier onset of age-related diseases (e.g., cardiovascular disease (CVD)) and thus contribute to sexually dimorphic morbidity and lifespan. However, the details regarding the emergence of this sex-biased methylation pattern remain unclear. RESULTS: To address these issues, we collected publicly available peripheral blood methylation datasets detected by Illumina HumanMethylation450 BeadChip platform from four studies that contain age and gender information of samples. We analyzed peripheral blood methylation data screened from 708 subjects of European ancestry. Results revealed a significant methylation change acceleration in middle-aged males (40-50 years old), which was further supported by another cohort containing 2711 subjects with Indian ancestry. Additional analyses suggested that these sexually dimorphic methylation changes were significantly overrepresented in genes associated with CVD, which may impact the potential activation of disease expression. Furthermore, we showed that higher prevalence of drinking and smoking in the males has some contribution to the sex-based methylation patterns during aging. CONCLUSION: Our results indicated that the sex-biased methylation changes occurred in middle-aged men in an acceleration manner and likely contribute to the sexual dimorphism observed in human lifespan by promoting the occurrence of CVD. As drinking and smoking were also found to be associated with this accelerated methylation change in men, it is possible that male lifespan may be prolonged by improving unhealthy lifestyles at or before middle age.

A Normalization-Free and Nonparametric Method Sharpens Large-Scale Transcriptome Analysis and Reveals Common Gene Alteration Patterns in Cancers.

Heterogeneity in transcriptional data hampers the identification of differentially expressed genes (DEGs) and understanding of cancer, essentially because current methods rely on cross-sample normalization and/or distribution assumption-both sensitive to heterogeneous values. Here, we developed a new method, Cross-Value Association Analysis (CVAA), which overcomes the limitation and is more robust to heterogeneous data than the other methods. Applying CVAA to a more complex pan-cancer dataset containing 5,540 transcriptomes discovered numerous new DEGs and many previously rarely explored pathways/processes; some of them were validated, both in vitro and in vivo, to be crucial in tumorigenesis, e.g., alcohol metabolism (ADH1B), chromosome remodeling (NCAPH) and complement system (Adipsin). Together, we present a sharper tool to navigate large-scale expression data and gain new mechanistic insights into tumorigenesis.

NCAPH plays important roles in human colon cancer.

Colon cancer (CC) is one of the major malignancies worldwide, whose pathogenesis is complex and requires the accumulated alteration of multiple genes and signaling pathways. Condensins are multi-protein complexes that play pivotal roles in chromosome assembly and segregation during mitosis, meiosis and even tumorigenesis. Using tissue microarrays by immunohistochemistry and hematoxylin-eosin staining, we found that non-SMC condensin I complex subunit H (NCAPH) in colon cancerous tissues was higher than that in all corresponding adjacent non-cancerous tissues. We then characterized the exact function of the NCAPH in CC. We provided evidences showing that NCAPH is highly expressed in colorectal cancer cell lines comparing with normal human colonic epithelial cells, and identified many NCAPH mutations in CC patients. We found that depletion of NCAPH inhibits CC cell proliferation, migration in vitro and xenograft tumor formation in vivo. Furthermore, NCAPH knockdown promotes cell apoptosis and cell cycle arrest at G2/M phase. Interestingly, the NCAPH high expression in tumor tissues of colon patients had a significantly better prognosis and survival rate than low-expression patients, suggesting that NCAPH high expression promotes colonic cancerous cell proliferation; on the other hand, it may also sensitize these cells responding to chemo- or radio-therapies. Collectively, these findings reveal an important role of NCAPH in CC, indicating that NCAPH could be used as a new therapeutic target in future.

ERCC6L, a DNA helicase, is involved in cell proliferation and associated with survival and progress in breast and kidney cancers.

By analyzing 4987 cancer transcriptomes from The Cancer Genome Atlas (TCGA), we identified that excision repair cross-complementation group 6 like (ERCC6L), a newly discovered DNA helicase, is highly expressed in 12 solid cancers. However, its role and mechanism in tumorigenesis are largely unknown. In this study, we found that ERCC6L silencing by small interring RNA (siRNA) or short hairpin RNA (shRNA) significantly inhibited the proliferation of breast (MCF-7, MDA-MB-231) and kidney cancer cells (786-0). Furthermore, ERCC6L silencing induced cell cycle arrest at G0/G1 phase without affecting apoptosis. We then performed RNA sequencing (RNA-seq) analysis after ERCC6L silencing and identified that RAB31 was markedly downregulated at both the transcriptional and translational levels. Its downstream protein, phosphorylated MAPK and CDK2 were also inhibited by ERCC6L silencing. The xenograft experiment showed that silencing of ERCC6L strikingly inhibited tumor growth from the 7th day after xenograft in nude mice. In addition, higher ERCC6L expression was found to be significantly associated with worse clinical survival in breast and kidney cancers. In conclusion, our results suggest that ERCC6L may stimulates cancer cell proliferation by promoting cell cycle through a way of RAB31-MAPK-CDK2, and it could be a potential biomarker for cancer prognosis and target for cancer treatment.

Large-scale DNA methylation expression analysis across 12 solid cancers reveals hypermethylation in the calcium-signaling pathway.

Tumorigenesis is linked to the role of DNA methylation in gene expression regulation. Yet, cancer is a highly heterogeneous disease in which the global pattern of DNA methylation and gene expression, especially across diverse cancers, is not well understood. We investigated DNA methylation status and its association with gene expressions across 12 solid cancer types obtained from The Cancer Genome Atlas. Results showed that global hypermethylation was an important characteristic across all 12 cancer types. Moreover, there were more epigenetically silenced than epigenetically activated genes across the cancers. Further analysis identified epigenetically silenced genes shared in the calcium-signaling pathway across the different cancer types. Reversing the aberrant DNA methylation of genes involved in the calcium-signaling pathway could be an effective strategy for suppressing cancers and developing anti-cancer drugs.

Exome-wide Association Study Identifies CLEC3B Missense Variant p.S106G as Being Associated With Extreme Longevity in East Asian Populations.

Life span is a complex trait regulated by multiple genetic and environmental factors; however, the genetic determinants of extreme longevity have been largely unknown. To identify the functional coding variants associated with extreme longevity, we performed an exome-wide association study (EWAS) on a Japanese population by using an Illumina HumanExome Beadchip and a focused replication study on a Chinese population. The EWAS on two independent Japanese cohorts consisting of 530 nonagenarians/centenarians demonstrated that the G allele of CLEC3B missense variant p.S106G was associated with extreme longevity at the exome-wide level of significance (p = 2.33×10-7, odds ratio [OR] = 1.50). The CLEC3B gene encodes tetranectin, a protein implicated in the mineralization process in osteogenesis as well as in the prognosis and metastasis of cancer. The replication study consisting of 448 Chinese nonagenarians/centenarians showed that the G allele of CLEC3B p.S106G was also associated with extreme longevity (p = .027, OR = 1.51), and the p value of this variant reached 1.87×10-8 in the meta-analysis of Japanese and Chinese populations. In conclusion, the present study identified the CLEC3B p.S106G as a novel longevity-associated variant, raising the novel hypothesis that tetranectin, encoded by CLEC3B, plays a role in human longevity and aging.

Insights into long noncoding RNAs of naked mole rat (Heterocephalus glaber) and their potential association with cancer resistance.

BACKGROUND: Long noncoding RNAs (lncRNAs) are a class of ubiquitous noncoding RNAs and have been found to act as tumor suppressors or oncogenes, which dramatically altered our understanding of cancer. Naked mole rat (NMR, Heterocephalus glaber) is an exceptionally long-lived and cancer-resistant rodent; however, whether lncRNAs play roles in cancer resistance in this seductive species remains unknown. RESULTS: In this study, we developed a pipeline and identified a total of 4422 lncRNAs across the NMR genome based on 12 published transcriptomes. Systematic analysis revealed that NMR lncRNAs share many common characteristics with other vertebrate species, such as tissue specificity and low expression. BLASTN against with 1057 human cancer-related lncRNAs showed that only 5 NMR lncRNAs displayed homology, demonstrating the low sequence conservation between NMR lncRNAs and human cancer-related lncRNAs. Further correlation analysis of lncRNAs and protein-coding genes indicated that a total of 1295 lncRNAs were intensively coexpressed (r ≥ 0.9 or r ≤ -0.9, cP value ≤ 0.01) with potential tumor-suppressor genes in NMR, and 194 lncRNAs exhibited strong correlation (r ≥ 0.8 or r ≤ -0.8, cP value ≤ 0.01) with four high-molecular-mass hyaluronan related genes that were previously identified to play key roles in cancer resistance of NMR. CONCLUSION: In this study, we provide the first comprehensive genome-wide analysis of NMR lncRNAs and their possible associations with cancer resistance. Our results suggest that lncRNAs may have important effects on anticancer mechanism in NMR.