Yongfei Hu

Connect the dots: a systems level approach for analyzing the miRNA-mediated cell death network.

In recent years, substantial research interests have arisen to decipher miRNA function in cell death modules such as apoptosis and autophagy. Despite enormous success, it is increasingly evident that systems biology approaches that analyze the intra- and inter-modular connectivity are essential to uncover the generic organizing principles of the miRNA-mediated cell death network. We therefore constructed the miRDeathDB database to archive experimentally confirmed programmed cell death (PCD)-associated miRNAs together with their target proteins. Based on global analysis of the miRNA-mediated cell death network, we find there are two classes of miRNAs important to the cell death output. One class tends to have more regulatory links to proteins within death modules, whereas the other one lies on the boundary between modules, and tends to connect with more protein pairs across the modules. These findings indicate that miRNAs provide a novel communication mechanism between PCD-related proteins involved in both intra- and inter-cell death modules. Furthermore, miRDeathDB can also facilitate researcher access to a variety of resources centered on PCD-associated miRNAs.

Mammalian ncRNA-disease repository: a global view of ncRNA-mediated disease network

Dear Editor  Recently, substantial studies have begun to explore the functional diversity and mechanistic roles of ncRNAs in mammals.1 Now, it has become increasingly apparent that ncRNAs are involved in multiple major biological processes, such as developmental timing, fat metabolism and cell death.2 Furthermore, the epigenetic and genetic defects in ncRNAs and their processing machinery have been implicated in the etiology of many forms of diseases.3 Several databases that documented the relevance of the microRNAs(miRNAs) to diseases have been constructed and provided useful results.4, 5 However, miRNAs are just the tip of the iceberg, other ncRNAs such as long non-coding RNAs (lncRNAs), PIWI-interacting RNAs (piRNAs) and small nucleolar RNAs (snoRNAs) have also been demonstrated to contribute to diseases.3, 6 Accumulated evidence suggest the diverse non-coding RNAs (ncRNAs) involved in a wide variety of diseases progression.3, 6, 7 It is a key challenge for understanding the precise behavior of diverse ncRNAs in mammalian diseases and deciphering the cross-regulations among disease-associated ncRNAs. Because there was no repository focused on diverse ncRNA-disease relationships in mammals, we have developed a manually curated diverse ncRNA-disease repository (MNDR, www.rna-society.org/mndr/) by integrating evidence in three mammals. Totally, 807 lncRNA-associated, 229 miRNA-associated, 13 piRNA-associated and 100 snoRNA-associated entries for 1149 curated entries were documented for three mammals (866 Homo sapiens-associated, 251 Mus musculus-associated and 32 Rattus norvegicus-associated entries) (Table 1). Table 1 The statistics of the ncRNA-disease entries in MNDR database Recent investigations indicated there are complex regulations among diverse ncRNAs and protein-coding genes. Such as, PTEN gene and the PTEN pseudogenes (ptenp1, one of lncRNAs) share a high degree of sequence homology, changes in ptenp1 expression levels indirectly affect PTEN expression by sequestering PTEN-targeting miRNAs.8 Thus understanding the mutual regulating pattern among diverse ncRNAs and protein-coding genes, particularly in disease conditions, is a key challenge. Thus, MNDR is not only a knowledge depository but providing us a good opportunity to view the ncRNA-mediated disease network globally (in visualization page: www.rna-society.org/mndr/visualization.html). Diverse ncRNAs and interaction genes were represented as nodes and the regulations were denoted as edges. Based on such a simplified ncRNA-mediated disease network, interesting observations have been achieved. The result showed that snoRNA htr, as a hub node, has intensively linked to 21 interaction genes in the network. More important, through BCL2, BCL2L1 and BAX, the snoRNA htr can communicate with the lncRNA malat1 (Supplementary Figure 1). Another example is snoRNA htr and lncRNA h19 are linked by E2F1 and MYC. When combined with human disease-associated miRNA evidence from mir2disease database, lncRNAs, miRNAs and snoRNAs, together with their interaction/target genes, can be integrated into bigger expanding ncRNA-mediated disease network. The biggest sub-network has 129 nodes and 149 edges, involving 33 lncRNAs, 1 snoRNA, 19 miRNAs and 76 interaction protein-coding genes(Supplementary Figure 2). In this network, more regulations among diverse ncRNAs directly or indirectly via intermediate genes, lncRNA dgcr5, har1a and har1b, were connected with hsa-mir-21 via intermediate gene REST. Interestingly, hsa-mir-21 and snoRNA htr were linked by key anti-apoptosis gene BCL2. Similar results were observed that lncRNA dgcr5, har1a and har1b can also communicate with snoRNA htr through alternative route NFKB1-hsa-mir-9-REST. Hence, according to current data, the two pivot protein-coding genes (BCL2 and NFKB1) and several ncRNAs (lncRNA malat1, snoRNA htr and miRNA hsa-mir-21, has-mir-9) collectively play an important role in the ncRNA-mediated disease network (Supplementary Figure 2). Importantly, the crosstalk between lncRNA malat1 and miRNA hsa-mir-21 can be found conserved in mouse ncRNA-mediated disease network. Above observations indicated diverse ncRNAs could communicate with each other in disease state through some disease-associated genes in mammals, highlighting the complexity, conservative and plasticity of the regulatory relationships between diverse ncRNAs and protein-coding genes in diseases.

RAID: a comprehensive resource for human RNA-associated (RNA–RNA/RNA–protein) interaction

Transcriptomic analyses have revealed an unexpected complexity in the eukaryote transcriptome, which includes not only protein-coding transcripts but also an expanding catalog of noncoding RNAs (ncRNAs). Diverse coding and noncoding RNAs (ncRNAs) perform functions through interaction with each other in various cellular processes. In this project, we have developed RAID (http://www.rna-society.org/raid), an RNA-associated (RNA-RNA/RNA-protein) interaction database. RAID intends to provide the scientific community with all-in-one resources for efficient browsing and extraction of the RNA-associated interactions in human. This version of RAID contains more than 6100 RNA-associated interactions obtained by manually reviewing more than 2100 published papers, including 4493 RNA-RNA interactions and 1619 RNA-protein interactions. Each entry contains detailed information on an RNA-associated interaction, including RAID ID, RNA/protein symbol, RNA/protein categories, validated method, expressing tissue, literature references (Pubmed IDs), and detailed functional description. Users can query, browse, analyze, and manipulate RNA-associated (RNA-RNA/RNA-protein) interaction. RAID provides a comprehensive resource of human RNA-associated (RNA-RNA/RNA-protein) interaction network. Furthermore, this resource will help in uncovering the generic organizing principles of cellular function network.

ViRBase: a resource for virus-host ncRNA-associated interactions.

Increasing evidence reveals that diverse non-coding RNAs (ncRNAs) play critically important roles in viral infection. Viruses can use diverse ncRNAs to manipulate both cellular and viral gene expression to establish a host environment conducive to the completion of the viral life cycle. Many host cellular ncRNAs can also directly or indirectly influence viral replication and even target virus genomes. ViRBase (http://www.rna-society.org/virbase) aims to provide the scientific community with a resource for efficient browsing and visualization of virus-host ncRNA-associated interactions and interaction networks in viral infection. The current version of ViRBase documents more than 12 000 viral and cellular ncRNA-associated virus–virus, virus–host, host–virus and host–host interactions involving more than 460 non-redundant ncRNAs and 4400 protein-coding genes from between more than 60 viruses and 20 hosts. Users can query, browse and manipulate these virus–host ncRNA-associated interactions. ViRBase will be of help in uncovering the generic organizing principles of cellular virus–host ncRNA-associated interaction networks in viral infection.

ncRDeathDB: A comprehensive bioinformatics resource for deciphering network organization of the ncRNA-mediated cell death system

Programmed cell death (PCD) is a critical biological process involved in many important processes, and defects in PCD have been linked with numerous human diseases. In recent years, the protein architecture in different PCD subroutines has been explored, but our understanding of the global network organization of the noncoding RNA (ncRNA)-mediated cell death system is limited and ambiguous. Hence, we developed the comprehensive bioinformatics resource (ncRDeathDB, www.rna-society.org/ncrdeathdb) to archive ncRNA-associated cell death interactions. The current version of ncRDeathDB documents a total of more than 4600 ncRNA-mediated PCD entries in 12 species. ncRDeathDB provides a user-friendly interface to query, browse and manipulate these ncRNA-associated cell death interactions. Furthermore, this resource will help to visualize and navigate current knowledge of the noncoding RNA component of cell death and autophagy, to uncover the generic organizing principles of ncRNA-associated cell death systems, and to generate valuable biological hypotheses.

Network-based survival-associated module biomarker and its crosstalk with cell death genes in ovarian cancer

Ovarian cancer remains a dismal disease with diagnosing in the late, metastatic stages, therefore, there is a growing realization of the critical need to develop effective biomarkers for understanding underlying mechanisms. Although existing evidences demonstrate the important role of the single genetic abnormality in pathogenesis, the perturbations of interactors in the complex network are often ignored. Moreover, ovarian cancer diagnosis and treatment still exist a large gap that need to be bridged. In this work, we adopted a network-based survival-associated approach to capture a 12-gene network module based on differential co-expression PPI network in the advanced-stage, high-grade ovarian serous cystadenocarcinoma. Then, regulatory genes (protein-coding genes and non-coding genes) direct interacting with the module were found to be significantly overlapped with cell death genes. More importantly, these overlapping genes tightly clustered together pointing to the module, deciphering the crosstalk between network-based survival-associated module and cell death in ovarian cancer.

RAID v2.0: an updated resource of RNA-associated interactions across organisms

With the development of biotechnologies and computational prediction algorithms, the number of experimental and computational prediction RNA-associated interactions has grown rapidly in recent years. However, diverse RNA-associated interactions are scattered over a wide variety of resources and organisms, whereas a fully comprehensive view of diverse RNA-associated interactions is still not available for any species. Hence, we have updated the RAID database to version 2.0 (RAID v2.0, www.rna-society.org/raid/) by integrating experimental and computational prediction interactions from manually reading literature and other database resources under one common framework. The new developments in RAID v2.0 include (i) over 850-fold RNA-associated interactions, an enhancement compared to the previous version; (ii) numerous resources integrated with experimental or computational prediction evidence for each RNA-associated interaction; (iii) a reliability assessment for each RNA-associated interaction based on an integrative confidence score; and (iv) an increase of species coverage to 60. Consequently, RAID v2.0 recruits more than 5.27 million RNA-associated interactions, including more than 4 million RNA–RNA interactions and more than 1.2 million RNA–protein interactions, referring to nearly 130 000 RNA/protein symbols across 60 species.

MNDR v2.0: an updated resource of ncRNA–disease associations in mammals

Abstract Accumulating evidence suggests that diverse non-coding RNAs (ncRNAs) are involved in the progression of a wide variety of diseases. In recent years, abundant ncRNA–disease associations have been found and predicted according to experiments and prediction algorithms. Diverse ncRNA–disease associations are scattered over many resources and mammals, whereas a global view of diverse ncRNA–disease associations is not available for any mammals. Hence, we have updated the MNDR v2.0 database (www.rna-society.org/mndr/) by integrating experimental and prediction associations from manual literature curation and other resources under one common framework. The new developments in MNDR v2.0 include (i) an over 220-fold increase in ncRNA–disease associations enhancement compared with the previous version (including lncRNA, miRNA, piRNA, snoRNA and more than 1400 diseases); (ii) integrating experimental and prediction evidence from 14 resources and prediction algorithms for each ncRNA–disease association; (iii) mapping disease names to the Disease Ontology and Medical Subject Headings (MeSH); (iv) providing a confidence score for each ncRNA–disease association and (v) an increase of species coverage to six mammals. Finally, MNDR v2.0 intends to provide the scientific community with a resource for efficient browsing and extraction of the associations between diverse ncRNAs and diseases, including >260 000 ncRNA–disease associations.

Single-cell RNA sequencing highlights transcription activity of autophagy-related genes during hematopoietic stem cell formation in mouse embryos

ABSTRACT Accumulating evidence has demonstrated that macroautophagy/autophagy plays an essential role in self-renewal and differentiation in embryonic hematopoiesis. Here, according to the RNA sequencing data sets of 5 population cells related to hematopoietic stem cell (HSC) formation during mouse embryogenesis (endothelial cells, PTPRC/CD45− and PTPRC/CD45+ pre-HSCs in the E11 aorta-gonad-mesonephros (AGM) region, mature HSCs in E12 and E14 fetal liver), we explored the dynamic expression of mouse autophagy-related genes in this course at the single-cell level. Our results revealed that the transcription activity of autophagy-related genes had a substantial increase when endothelial cells (ECs) specified into pre-HSCs, and the upregulation of autophagy-essential genes correlated with reduced NOTCH signaling in pre-HSCs, suggesting the autophagy activity may be greatly enhanced during pre-HSC specification from endothelial precursors. In summary, our results presented strong evidence that autophagy plays a critical role in HSC emergence during mouse midgestation.

Transcriptomic insights into temporal expression pattern of autophagy genes during monocytic and granulocytic differentiation

ABSTRACT Macroautophagy/autophagy plays an essential role in hematopoietic stem cell (HSC) differentiation. However, the role of autophagy during monocytic and granulocytic differentiation remains poorly understood. Hence, we first represented global transcriptomic analysis for temporal expression of autophagy genes during monocytic and granulocytic differentiation by combining RNA-Seq data with monocytic and granulocytic induction in CD34+ hematopoietic stem and progenitor cells. According to a self-organizing map (SOM) algorithm, our results show temporal expression patterns of autophagy genes during monocytic and granulocytic differentiation. More importantly, 22 autophagy genes present significantly divergent roles during monocytic and granulocytic differentiation, indicating these autophagy genes could be important factors involved in the differentiation of myeloid progenitors into monocytes and granulocytes.