The National Genomics Data Center (NGDC), part of the China National Center for Bioinformation (CNCB), provides a suite of database resources to support worldwide research activities in both academia and industry. With the explosive growth of multi-omics data, CNCB-NGDC is continually expanding, updating and enriching its core database resources through big data deposition, integration and translation. In the past year, considerable efforts have been devoted to 2019nCoVR, a newly established resource providing a global landscape of SARS-CoV-2 genomic sequences, variants, and haplotypes, as well as Aging Atlas, BrainBase, GTDB (Glycosyltransferases Database), LncExpDB, and TransCirc (Translation potential for circular RNAs). Meanwhile, a series of resources have been updated and improved, including BioProject, BioSample, GWH (Genome Warehouse), GVM (Genome Variation Map), GEN (Gene Expression Nebulas) as well as several biodiversity and plant resources. Particularly, BIG Search, a scalable, one-stop, cross-database search engine, has been significantly updated by providing easy access to a large number of internal and external biological resources from CNCB-NGDC, our partners, EBI and NCBI. All of these resources along with their services are publicly accessible at https://bigd.big.ac.cn.

Database Resources of the National Genomics Data Center, China National Center for Bioinformation in 2021.

Aging is a major risk factor for many diseases, especially in highly prevalent cardiopulmonary comorbidities and infectious diseases including Coronavirus Disease 2019 (COVID-19). Resolving cellular and molecular mechanisms associated with aging in higher mammals is therefore urgently needed. Here, we created young and old non-human primate single-nucleus/cell transcriptomic atlases of lung, heart and artery, the top tissues targeted by SARS-CoV-2. Analysis of cell type-specific aging-associated transcriptional changes revealed increased systemic inflammation and compromised virus defense as a hallmark of cardiopulmonary aging. With age, expression of the SARS-CoV-2 receptor angiotensin-converting enzyme 2 (ACE2) was increased in the pulmonary alveolar epithelial barrier, cardiomyocytes, and vascular endothelial cells. We found that interleukin 7 (IL7) accumulated in aged cardiopulmonary tissues and induced ACE2 expression in human vascular endothelial cells in an NF-κB-dependent manner. Furthermore, treatment with vitamin C blocked IL7-induced ACE2 expression. Altogether, our findings depict the first transcriptomic atlas of the aged primate cardiopulmonary system and provide vital insights into age-linked susceptibility to SARS-CoV-2, suggesting that geroprotective strategies may reduce COVID-19 severity in the elderly.

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Single-cell transcriptomic atlas of primate cardiopulmonary aging.

Sirtuin 3 (SIRT3) is an NAD+-dependent deacetylase linked to a broad range of physiological and pathological processes, including aging and aging-related diseases. However, the role of SIRT3 in regulating human stem cell homeostasis remains unclear. Here we found that SIRT3 expression was downregulated in senescent human mesenchymal stem cells (hMSCs). CRISPR/Cas9-mediated depletion of SIRT3 led to compromised nuclear integrity, loss of heterochromatin and accelerated senescence in hMSCs. Further analysis indicated that SIRT3 interacted with nuclear envelope proteins and heterochromatin-associated proteins. SIRT3 deficiency resulted in the detachment of genomic lamina-associated domains (LADs) from the nuclear lamina, increased chromatin accessibility and aberrant repetitive sequence transcription. The re-introduction of SIRT3 rescued the disorganized heterochromatin and the senescence phenotypes. Taken together, our study reveals a novel role for SIRT3 in stabilizing heterochromatin and counteracting hMSC senescence, providing new potential therapeutic targets to ameliorate aging-related diseases.

SIRT3 consolidates heterochromatin and counteracts senescence

Abstract Aging is accompanied by the decline of organismal functions and a series of prominent hallmarks, including genetic and epigenetic alterations. These aging-associated epigenetic changes include DNA methylation, histone modification, chromatin remodeling, non-coding RNA (ncRNA) regulation, and RNA modification, all of which participate in the regulation of the aging process, and hence contribute to aging-related diseases. Therefore, understanding the epigenetic mechanisms in aging will provide new avenues to develop strategies to delay aging. Indeed, aging interventions based on manipulating epigenetic mechanisms have led to the alleviation of aging or the extension of the lifespan in animal models. Small molecule-based therapies and reprogramming strategies that enable epigenetic rejuvenation have been developed for ameliorating or reversing aging-related conditions. In addition, adopting health-promoting activities, such as caloric restriction, exercise, and calibrating circadian rhythm, has been demonstrated to delay aging. Furthermore, various clinical trials for aging intervention are ongoing, providing more evidence of the safety and efficacy of these therapies. Here, we review recent work on the epigenetic regulation of aging and outline the advances in intervention strategies for aging and age-associated diseases. A better understanding of the critical roles of epigenetics in the aging process will lead to more clinical advances in the prevention of human aging and therapy of aging-related diseases. 

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Epigenetic regulation of aging: implications for interventions of aging and diseases

Mitochondrial sirtuins, metabolism, and aging

Abstract Organismal aging is driven by interconnected molecular changes encompassing internal and extracellular factors. Combinational analysis of high-throughput ‘multi-omics’ datasets (gathering information from genomics, epigenomics, transcriptomics, proteomics, metabolomics and pharmacogenomics), at either populational or single-cell levels, can provide a multi-dimensional, integrated profile of the heterogeneous aging process with unprecedented throughput and detail. These new strategies allow for the exploration of the molecular profile and regulatory status of gene expression during aging, and in turn, facilitate the development of new aging interventions. With a continually growing volume of valuable aging-related data, it is necessary to establish an open and integrated database to support a wide spectrum of aging research. The Aging Atlas database aims to provide a wide range of life science researchers with valuable resources that allow access to a large-scale of gene expression and regulation datasets created by various high-throughput omics technologies. The current implementation includes five modules: transcriptomics (RNA-seq), single-cell transcriptomics (scRNA-seq), epigenomics (ChIP-seq), proteomics (protein–protein interaction), and pharmacogenomics (geroprotective compounds). Aging Atlas provides user-friendly functionalities to explore age-related changes in gene expression, as well as raw data download services. Aging Atlas is freely available at https://bigd.big.ac.cn/aging/index.

Aging Atlas: a multi-omics database for aging biology

Myocardial infarction (MI) is the irreversible cardiomyocyte death resulting from prolonged oxygen deprivation due to obstructed blood supply (ischemia), leading to contractile dysfunction and cardiac remodeling. In recent decades, stem cell transplantation has been extensively investigated for the repair of injured heart in animal studies and clinical trials (Kanelidis et al., 2017; Gyongyosi et al., 2018). Among cell-based therapies in clinical development, mesenchymal progenitor cells (MPCs) are attractive candidates due to their multi-lineage potential and immunomodulatory properties (Bagno et al., 2018). However, low quality (e.g., reduced proliferative ability and increased cellular senescence at late passages) and heterogeneous cell sources, as well as poor retention and survival rate of transplanted MPCs in an in vivo niche present obstacles towards broader clinical applications (Nguyen et al., 2016; Li et al., 2020). Forkhead box O3 (FOXO3), one of the most prominent genes related to human longevity, functions in diverse biological processes including DNA repair, oxidative stress response, cell proliferation and cellular senescence (Liu et al., 2018). We have previously reported that FOXO3 loss drives primate arterial aging and that constitutive activation of FOXO3 in human embryonic stem cell (hESC)-derived MPCs enhances their stress resistance and attenuates cellular senescence (Yan et al., 2019; Zhang et al., 2020). Here, we evaluated the cardiac repair after MI in immunodeficient mice intramyocardially transplanted with FOXO3-geneticallyenhanced MPCs (FOXO3-GE-MPCs). FOXO3-GE-MPCs were generated by directed differentiation of hESCs in which two FOXO3 phosphorylation sites were replaced with alanine (S253A, S315A) using targeted gene editing (Fig. S1A and S1B). The engineered FOXO3 could not be phosphorylated by AKT at S253 or S315 and was therefore constitutively active in the nucleus (Yan et al., 2019). Consistent with previous observations (Yan et al., 2019), FOXO3-GE-MPCs exhibited increased proliferation and decreased senescence-associated (SA)-β-gal activity relative to wildtype MPCs (WT-MPCs) (Fig. S1C–E). We next investigated whether FOXO3-GE-MPCs would be retained longer in the heart than WT-MPCs when intramyocardially delivered at the initiation of myocardial ischemia. In vivo imaging of luciferase-labelled MPCs revealed that transplanted WT-MPCs diminished within five days whereas FOXO3-GE-MPCs remained detectable until day 11 (Fig. 1A). Due to the limited resolution and sensitivity of in vivo imaging, we performed immunofluorescence staining of the human Golgi marker hTGN46 and RT-PCR of human GAPDH to further detect the transplanted cells in ischemic hearts and found that FOXO3 enhancement prolonged MPC retention up to 4 weeks after MI (Fig. 1B and 1C). Next, we used transthoracic echocardiography to explore whether FOXO3-GE-MPCs could ameliorate cardiac dysfunction and left ventricular (LV) remodeling after MI. In control mice (MI + vehicle group), we observed decreased cardiac contractility along with enlarged LV chamber at 4 weeks after MI. These effects were partially reversed by the transplantation with FOXO3-GE-MPCs, but not WT-MPCs (Fig. 1D). Similarly, an MI-induced increase in heart to body weight ratio and a decrease in running distance (Fig. 1E), along with cardiac fibrosis, compensatory hypertrophy and cardiomyocyte apoptosis, were all ameliorated only by FOXO3-GE-MPC transplantation (Figs. 1F–H and S1F). Collectively, our data indicate that FOXO3 enhancement promotes cardiac repair by MPCs after MI, suggesting that FOXO3-GE-MPCs may provide effective biomaterials for stem cell-based therapy against ischemic heart diseases. To dissect the underlying mechanisms of cardiac repair by FOXO3-GE-MPCs, we performed RNA-seq analysis of heart tissues of the infarct border zone (Figs. 2A, 2B and S1G–J) and identified a panel of MI-upregulated genes that were reversed by the transplantation of FOXO3-GE-MPCs, including those involved in inflammatory response (Fig. 2B). In addition, RelA (p65) that is a subunit of the NF-κB transcription complex (Wang et al., 2018) was upregulated in ischemic hearts and its upregulation was attenuated only by the transplantation with FOXO3-GE-MPCs (Figs. 2C and S1K). Some of the MI-upregulated genes rescued upon FOXO3-GE-MPC transplantation were enriched in NF-κB pathway (Fig. S1L). Furthermore, several NF-κB target genes including Cxcl13, Mmp9, Itgam, Tlr2 and Hmox1 were

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Wang Kang

Papers

Aging Atlas: a multi-omics database for aging biology

FOXO3-engineered human mesenchymal progenitor cells efficiently promote cardiac repair after myocardial infarction