interactions of rna with other biomolecules are fundamental in cellular processes . in particular , noncoding rna  protein interactions play important roles in protein synthesis ( 1,2 ) , gene expression ( 3,4 ) , rna processing ( 57 ) , developmental regulation ( 8,9 ) , etc .
some lncrnas function as transcriptional regulators through direct association with transcription factors ( 1012 ) , while others indirectly interact with proteins in cooperation with genomic dnas ( 13 ) .
the functional importance of many ncrna  protein interactions for correct transcriptional regulation has been demonstrated ( 1419 ) , suggesting wide - ranging effects of ncrna  protein interaction .
in addition to targeting or being targeted by proteins or protein - coding transcripts , ncrnas could also potentially target other ncrnas , resulting in a layer of regulatory interactions between noncoding rna classes ( 11,20 ) . consequently , cataloguing interactions of ncrnas and other biomolecules is significant for gaining insight into biological processes and understanding the mechanism by which ncrnas carry out their regulatory function . given the importance of ncrna interactions in various pathways , we embarked on a project to build a comprehensive catalogue of such data and established the npinter database ( 21 ) . a large amount of new research has led to deeper insight into ncrna interactions at a variety of levels ; thus , npinter has been updated to v2.0 to accommodate for such expanding data resources . following data collection as described below , noncoding molecules in npinter were automatically filtered and assigned identifiers from noncode ( 22 ) or mirbase ( 23 ) , while protein - coding molecules were assigned identifiers from uniprot ( 24 ) , refseq ( 25 ) or unigene ( 26 ) . with the exception of rrnas and trnas , all reported interactions of ncrnas were included .
the aim of the database is to provide a platform that will facilitate both bioinformatic as well as experimental research .
in addition to a user - friendly interface and a convenient search option that allow efficient recovery of related interactions and other information , npinter v2.0 also provides a visualization platform for related interactions .
based on the first version of npinter database , new datasets from literature and other related databases were collected . in this update , data from literature accounts for the major source .
we first retrieved literature published in the last 5 years from pubmed , employing key words including 
clip interaction ,  non - coding rna bind protein post - transcriptional ,  rna  rna interaction ,  lncrna protein interaction ,  lncrna bind ,  rna protein cross linking ,  rip non - coding rna , etc , and found 1270 relevant articles .
information on reported interactions , either verified by experiments or derived from binding sites generated by sequencing , was manually extracted . for the latter , we only extracted processed data by authors , rather than raw sequencing data .
binding sites were first compared with refseq coding genes to eliminate those located within coding regions and then screened against noncode , which serves as an ncrna reference database .
binding sites that lie within noncode ncrnas were retained and assigned noncode ids , while others were discarded . as interaction partners , proteins , protein - coding rnas and dna were assigned uniprot ids , refseq ids and unigene ids , respectively , while other noncoding rnas and dna were still assigned noncode ids or mirbase ids .
we also integrated data from external resources , mainly lncrnadisease ( 27 ) , which curated 478 experimentally supported lncrna interactions at various levels , including binding , regulation and co - expression .
curation on data from literature and integration of data from lncrnadisease , npinter v2.0 provides a multilevel snapshot of the interactome .
a process of redundancy elimination was then performed on the whole dataset , including previously existing data and newly collected data as mentioned above .
the workflow used for the generation of npinter is schematically shown in figure 1 . 

rna binding sites of individual proteins identified using genome - wide techniques were screened against noncode and only those correspond to noncode rnas were extracted .
rna binding sites of individual proteins identified using genome - wide techniques were screened against noncode and only those correspond to noncode rnas were extracted .
the purpose of the database is to serve as a knowledge base for experimentally - oriented studies and as a resource for bioinformatics applications .
the first release of npinter in 2006 contained 700 published functional interactions from six model organisms .
npinter v2.0 presently contains 201 107 ncrna interactions distributed on 18 organisms , collected from 529 published articles .
the significant growth in the amount of data is primarily because of systematic identification of protein binding sites on the transcriptome through a combination of clip and rna sequencing , whereas other interactions , including ncrna  rna interactions and transcript factor ( tf)ncrna interactions , were obtained mainly from interaction studies on individual ncrna .
the basic information on each interaction contains an interaction i d , name of ncrna and its interaction partner , organism in which the interaction was identified , level and class of interaction manually defined in npinter , as well as tags manually added .
for example , at the binding level , which accounts for most of the npinter datasets , ncrnas may interact with dna ( 13,28 ) , ncrna ( 29 ) , mirna ( 30 ) , mrna ( 31 ) and protein ( 32 ) . at the level of indirect interactions
, ncrnas may either regulate or be regulated by an interaction partner ( 33,34 ) .
the level of interaction defined in npinter represents the types of interacting molecules and characteristics of the interaction , including  rna 
protein ,  rna  rna and  dna  tf. in general , npinter classifies all interactions into three classes , which are 
regulatory and  co - expression. tags are added to give brief introductions to each interaction , suggesting in which biological process the interaction participates .
mirna ,  mirna target interaction ,  ncrna affects synthesis or function of protein ,  ncrna is regulated ,  ncrna  protein binding ,  expression , processing , or function of ncrna is affected ,  ncrna targets mrna ,  other linkages ,  promoter as action site ,  regulatory and  rna  rna interaction. each interaction can be labelled simultaneously with several tags .
the npinter database is composed of three linked tables : 
 the interaction table gives a description of details of the interaction between two molecules .
for example , for the interaction between kcnq1ot1 and dnmt1 in mouse , information in this table states that this interaction occurs at the level of  rna  protein and is classified into 
protein binding.the molecule table describes information on interacting molecules , containing identifiers from unigene , noncode , mirbase , refseq or uniprot as well as the name , aliases and description of each molecule in npinter.the reference table gives the details of literature references in the interaction table .
each record in the table includes the medline standard article code ( pmid ) as well as general publication information . 
 
for example , for the interaction between kcnq1ot1 and dnmt1 in mouse , information in this table states that this interaction occurs at the level of  rna  protein and is classified into  binding class with a tag  ncrna 
protein binding. the molecule table describes information on interacting molecules , containing identifiers from unigene , noncode , mirbase , refseq or uniprot as well as the name , aliases and description of each molecule in npinter .
each record in the table includes the medline standard article code ( pmid ) as well as general publication information .
users can also query the database through the search interface , using the name or aliases of molecules , molecule ids or any other descriptive words .
the whole datasets of npinter can be directly downloaded from the webpage , and the results of each search can be exported . in the updated version of the database
, we have also integrated the online blast service ( ncbi wwwblast version 2.2.17 ) , which allows sequence similarity searches for both nucleotide and peptide to be run on npinter entries . importantly
, for a noncoding rna with no recognized name or identified function , it is also possible to search its potential interactions with other molecules in npinter simply based on its sequence . additionally , npinter also offers a graph - based visualization of interactions ( figure 2 ) . in the visualization graph , each molecule is a node and interactions between molecules are designated as edges .
red nodes represent proteins or protein - coding rnas and dna , while blue and pink nodes represent ncrnas and mirnas , respectively .
information of each molecule can be checked in a new window by clicking on the corresponding node .
the colour of the edges discriminates the source of each interaction , green suggesting the interaction is from npinter and purple suggesting the interaction is from string ( 35 ) .
the location of the nodes is determined by the forcedirected layout algorithm as implemented in cytoscape web ( 36 ) .
the graph can be opened in the stand - alone webpage to produce high resolution images in which size , colour and location of nodes and edges can be adjusted . to maintain an up - to - date and comprehensive resource
, we encourage users to submit newly published ncrna interactions , with pubmed accession numbers required . 

the initial placement of the nodes is determined by a  force - directed layout algorithm that aims to keep the more similar nodes closer together , but the placement may later be adjusted by the user .
the initial placement of the nodes is determined by a  force - directed layout algorithm that aims to keep the more similar nodes closer together , but the placement may later be adjusted by the user .
noncoding rnas have emerged as key molecular players in different biological processes ( 37 ) . characterizing ncrna interactions will largely contribute towards the discovery of novel ncrna functions . however , existing databases are not enough to provide a comprehensive resource for such a purpose .
for example , starbase ( 38 ) lists all binding sites of several proteins in the transcriptome , but there is no specific annotation for noncoding transcripts . for another example , npidb ( 39 ) focuses on nucleic acid  protein complexes from pdb , thus , most rnas included are either rrnas or trnas .
in contrast , npinter is more informative on ncrna interactions than other databases , with aims on integrating interactions of the other types of ncrnas that serve a variety of functions . in other words
, npinter is one of the most comprehensive databases of interactions between ncrnas and other biomolecules .
compared with the previous version of npinter , the new version is a step towards a more integrated knowledge database . the total number of functional interactions of ncrnas has been expanded .
npinter v2.0 is also developed to present graphical molecular interaction networks that will enable biological scientists to explore their data in a more systems - oriented manner .
the authors plan to update npinter whenever there is an accumulation of novel ncrna interactions reported in literature or other sources .
it is worth mentioning that npinter is included in our systematic platform for noncoding rnas .
our platform consists of ncrna resources such as noncode and npinter , as well as online tools and web servers ( 4043 ) including cnci ( 40 ) and ncfans ( 43 ) for analysis of ncrnas . as a member of the union of specific databases and tools for noncoding rnas ,
npinter is expected to remain an informative and valuable data source on the biological roles of ncrnas for the scientific community .
funding for open access charge : national high - tech research and development projects 863 [ 2012aa020402 ] ; training program of the major research plan of the national natural science foundation of china ; national natural science foundation of china ; chinese academy of science strategic project of leading science and technology [ xda01020402 ] ; national key basic research and development program 973 [ 2009cb825401 ] ; the national center for mathematics and interdisciplinary sciences .
 npinter ( http://www.bioinfo.org/npinter ) is a database that integrates experimentally verified functional interactions between noncoding rnas ( excluding trnas and rrnas ) and other biomolecules ( proteins , rnas and genomic dnas ) . 
 extensive studies on ncrna interactions have shown that ncrnas could act as part of enzymatic or structural complexes , gene regulators or other functional elements . with the development of high - throughput biotechnology , such as cross - linking immunoprecipitation and high - throughput sequencing ( clip - seq ) , 
 the number of known ncrna interactions , especially those formed by protein binding , has grown rapidly in recent years . in this work , we updated npinter to version 2.0 by collecting ncrna interactions from recent literature and related databases , expanding the number of entries to 201 107 covering 18 species . 
 in addition , npinter v2.0 incorporated a service for the blast alignment search as well as visualization of interactions . 
INTRODUCTION
DATA COLLECTION AND ANNOTATION
DATABASE CONTENT AND STRUCTURE
DATA ACCESS AND VISUALIZATION
CONCLUSION
SUPPLEMENTARY DATA
FUNDING