IEEE/ACM TRANSACTIONS ON COMPUTATIONAL BIOLOGY AND BIOINFORMATICS, VOL. 19, NO.

1, JANUARY/FEBRUARY 2022 255

A Heterogeneous Information Network Model for

Long Non-Coding RNA Function Prediction
Sunil Kumar P V , Adheeba Thahsin , Manju M, and Gopakumar G

Abstract—Exciting information on the functional roles played by long non-coding RNA (lncRNA) has drawn substantial research
attention these days. With the advent of techniques such as RNA-Seq, thousands of lncRNAs are identified in very short time spans.
However, due to the poor annotation rate, only a few of them are functionally characterised. The wet lab experiments to elucidate
lncRNA functions are challenging, slow progressing and sometimes prohibitively expensive. This work attempts to solve the crucial
problem of developing computational methods to predict lncRNA functions. The model presented here, predicts the functions of
lncRNAs by making use of a meta-path based measure, AvgSim on a Heterogeneous Information Network (HIN). The network is
constructed from existing protein and function association data of lncRNAs, lncRNA co-expression data and protein protein interaction
data. Out of the 2,758 lncRNA considered for the experiment, the proposed method predicts possible functions for 2,695 lncRNAs with
an accuracy of 73.68 percent and found to perform better than the other state-of-the-art approaches for an independent test set. A case
study of two well-known lncRNAs (HOTAIR and H19) is conducted and the associated functions are identified. The results were
validated using experimental evidence from the literature. The script and data used for the implementation of the model is freely
available at: http://bdbl.nitc.ac.in/LncFunPred/index.html.

Index Terms—LncRNA, heterogeneous information network, meta-path, classification, random forest, AvgSim

1 INTRODUCTION annotate lncRNA functions are expensive, time consuming

and tiresome [6]. Thus the development of computational
non-coding RNAs are RNA transcripts longer than
L ONG
200 nucleotides. They lack key properties such as pro-
tein coding potential and sequence conservation, which are
alternatives that predict lncRNA functions is a pressing
requirement in lncRNA research.
The naive approaches to predict functions of biomole-
inevitable for functional roles [1], [2]. Until a decade ago,
cules require excessive usage of their sequence and struc-
genomics considered most of the non-coding sections of
tural information. However, this strategy is ineffective for
RNA as ‘junk’, containing no useful genetic information.
lncRNAs due to their low sequence conservation and poor
However, recent studies suggest that lncRNAs are involved
knowledge about the structure-function association. Conse-
in numerous biological activities like cell-type specific
quently, a new realm of research emerged wherein network
expression, localization to sub-cellular components, associa-
science is applied lncRNA research. The network-based
tion with human diseases and many more [3]. These biologi-
approaches rely more on the implicit information contained
cal and cellular properties implicate lncRNAs’ functionality
in the network than biological features of lncRNAs. Hence,
and they are no longer considered as ‘junk’ [4], [5].
such efforts became popular in short time spans.
Although a large number of lncRNAs have been identi-
Network-based methods have their foundation on two
fied so far, the number of properly annotated lncRNAs is
principles. First is “Guilt by association” principle which
not very exciting. The gap between rates of discovery and
states that genes regulating a biological process may be co-
annotation of lncRNAs account for the limited functional
expressed with genes involved in the same process [7]. The
knowledge about lncRNAs. Wet lab experiments to
second one is that biomolecules do interact with each other
while performing a function [8]. Therefore, while designing

S.K. P V is with the Department of Computer Science and Engineering, a model that predicts the functions of lncRNAs, the interac-
National Institute of Technology Calicut, NIT Campus (PO), Kozhikkode, tions of lncRNAs including their co-expression deserve pre-
Kerala 673601, India, and also with the Department of CSE, CMR Insti- dominant consideration.
tute of Technology Bangalore, AECS Layot (PO), Bangalore, Karnataka
560037, India. E-mail: sunilkumarpv_p130073cs@nitc.ac.in. Majority of the existing approaches for computational

A. Thahsin and G. G are with the Department of Computer Science and prediction of lncRNA functions use the interactive relation-
Engineering, National Institute of Technology Calicut, NIT Campus ships between lncRNA and protein as the primary input to
(PO), Kozhikkode, Kerala 673601, India.
E-mail: adeeba.thahsin@gmail.com, gopakumarg@nitc.ac.in.
construct the networks. Liao Q et al. [9] constructed coding

M. M is with the Department of Zoology, KSM Devaswom Board College non-coding gene co-expression network (CNC) and
Sasthamkotta, Kollam, Kerala 690521, India. assigned functions to around 340 lncRNAs based upon the
E-mail: manjugopkumar@gmail.com. functions of its neighbourhood proteins. This work was one
Manuscript received 14 Aug. 2018; revised 27 Feb. 2020; accepted 3 June 2020. of the initial attempts towards lncRNA function prediction.
Date of publication 8 June 2020; date of current version 3 Feb. 2022. Here the possibility of protein interactions was not consid-
(Corresponding author: Sunil Kumar P V.)
Recommended for acceptance by R. Backofen. ered. A global lncRNA function prediction tool (lnc-GFP)
Digital Object Identifier no. 10.1109/TCBB.2020.3000518 was developed by Xingli Guo et al. [10] by incorporating
1545-5963 ß 2020 IEEE. Personal use is permitted, but republication/redistribution requires IEEE permission.
See ht_tps://www.ieee.org/publications/rights/index.html for more information.

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 256 IEEE/ACM TRANSACTIONS ON COMPUTATIONAL BIOLOGY AND BIOINFORMATICS, VOL. 19, NO. 1, JANUARY/FEBRUARY 2022
protein interaction data into the co-expression network used
in Liao et al. They annotated 1,625 lncRNAs with functional
characteristics. But none of these methods used Next Gener-
ation Sequencing (NGS) data for processing. Later on, Yun
Xiao et al. [11] used a Bayesian network of lncRNA and pro-
tein using the transcript profile made from RNA-Seq data.
This method assigned functions to 762 lncRNAs by func-
tional enrichment of highly interconnected proteins. To
annotate ncRNA functions, Feng Chen and Yi-Ping Phoebe
Chen [12] have applied bridging rule mining. They have
used two different measures to explore the relationship
between ncRNAs, one as the linearity measure and the
other the non-linearity measure. Then based on the associa-
tion rule, functions of ncRNAs are speculated. But this
method is not exclusively devoted to lncRNAs. Qinghua
Jiang et al. [13] performed hypergeometric test on lncRNA-
protein co-expression data from RNA-Seq to predict
lncRNA function. They mapped 9,625 lncRNAs to their
function as well as pathways.
All the network-based methods found in current litera-
ture focus on lncRNA-protein interaction as a crucial metric
to devise a model that predicts the functions of lncRNAs.
Hence these methods can predict the functions of lncRNAs
that have known protein associations. In order to exploit the
fullest advantage of a network based model, the lncRNA-
lncRNA links are also to be taken in to account. The pro-
posed work considers lncRNA-lncRNA links as well and
predicts the functions of lncRNAs even in the absence of
known protein associations.
Here, the problem of predicting functions of lncRNAs
which do not have known protein association is addressed
by the incorporation of lncRNA co-expression data. A Het-
erogeneous Information Network (HIN) is built with
lncRNA, protein and function as node types and (a) pro-
tein-protein interaction, (b) protein-function association, (c)
lncRNA-protein interaction, (d) lncRNA co-expression, and
(e) known lncRNA-function association as edge types. The
application of the method AvgSim to quantify the degree of
relatedness of a pair of nodes in the HIN is inspired from
the work by J. Yang et al. [14], who adopted AvgSim from
the proposal by D. Xiao et al. [15].
LncRNA-function pairs can be connected through vari-
ous paths termed as meta-paths in HIN terminology. Each
meta-path carries a semantic meaning, which needs to be
interpreted properly. If an lncRNA is connected to a func-
tion through a protein node, the path is ‘lncRNA-protein-
function’ and its semantic meaning is that the function is
performed by lncRNA through protein interaction. Simi-
larly, meta-path ‘lncRNA-lncRNA-function’ is interpreted
as the function is performed by lncRNA molecules, in com-
bination. Meta-paths and their semantic meanings are dis-
cussed in more detail in Section 2.2.
After the HIN construction, the functionally relevant
meta-paths are extracted through a correlation analysis.
The relatedness measure, AvgSim is computed along such
relevant meta-paths. The AvgSim score along various meta-
paths are combined to form the features for a Random For-
est classifier which performs the prediction of lncRNA
functions.
In contrast to the existing methods which use only
lncRNA-protein interaction, the proposed work exploits
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meta-path based information of HIN for prediction. Possible
functions are assigned to a total of 2,695 lncRNAs by the
method. The correctness is verified statistically by cross-
validation and reconfirmed through mining recent litera-
ture. A case study of two well-studied lncRNAs is also
conducted and results are validated.
The rest of the paper is organised as follows: Section 2
deals with the input data, methodologies and algorithms
used for the construction of the prediction model. Various
statistical parameters used to validate the prediction perfor-
mance of the model and the details of the classifier used are
also outlined. Section 3 explains the results obtained. A
detailed discussion on the implications of the results is pro-
vided in Section 4. The outcomes of a case study conducted
forms the matter for Section 5. Section 6 provides the con-
cluding remarks and future directions.
2 MATERIALS AND METHODS
This section describes the formulation of the prediction
model and derivation of data set to conduct the experi-
ments. To begin with, the major HIN concepts used further
in the discussion are formally defined.
Heterogeneous Information Network
An Information Network [17], [18] is defined as a directed
graph G ¼ ðV; EÞ with an object type mapping function
f : V ! A and a link type mapping function c : E ! R,
where each object v 2 V belongs to one particular object
type fðvÞ 2 A, each link e 2 E belongs to a particular rela-
tion cðeÞ 2 R, and if two links belong to the same relation
type, the two links share the same starting object type as
well as the ending object type.
The information network is called heterogeneous infor-
mation network if the number of types of objects jAj > 1 or
relations jRj > 1.
Network Schema
The network schema [17], [18], denoted as TG ¼ ðA; RÞ, is
a meta-template for an information network G ¼ ðV; EÞ
with the object type mapping f : V ! A and the link type
mapping c : E ! R, which is a directed graph defined over
object types A, with edges as relations from R. The network
schema of a heterogeneous information network specifies
type constraints on the sets of objects and relationships
among the objects.
Meta-Path
A meta-path [17], [18], P is a path defined on a schema
R1 R2
TG ¼ ðA; RÞ, and is denoted in the form A1
! A2
!
Rl
  
! Alþ1 which defines a composite relation R ¼ R1  R2 
. . .  Rl between objects A1 ; A2 ; . . .; Alþ1 where  denotes the
composition operator on relations.
2.1 Heterogeneous LncRNA-Protein-Function
Network (HLPFN)
Heterogeneous LncRNA-Protein-Function Network (HLPFN)
is a heterogeneous interconnection of five different interaction
networks constructed from protein interactions, lncRNA co-
expression, lncRNA functional associations, and lncRNA-pro-
tein interactions and protein-function association. All relation-
ships are kept as separate adjacency matrices to maintain the
heterogeneity of nodes and edges. The various adjacency
 V ET AL.: HETEROGENEOUS INFORMATION NETWORK MODEL FOR LONG NON-CODING RNA FUNCTION PREDICTION
matrices used to construct HIN are shown in Fig. 1a. The con-
struction of the adjacency matrices of the individual networks
is described below.
2.1.1 LncRNA-Protein Interaction Network
LncRNA-protein interaction data is collected from NPInter 3.0
[19]. It contains interaction of ncRNAs with different kinds of
biomolecules. The lncRNAs are filtered from ncRNA using
NONCODE ID [20] and the interaction level is restricted to
‘RNA-protein’ to retrieve proteins. The interactions are
restricted to ‘Homo Sapiens’. The lncRNA-protein interaction
network is represented as an adjacency matrix with row
names as lncRNAs, and column names as proteins. The edges
are added based on interaction data collected. The construc-
tion of adjacency matrix MLP is as follows:

1; if LncRNAi interacts with Proteinj
MLP ði; jÞ ¼ : 1; if Proteini has Functionj
0; otherwise
2.1.2 Protein-Protein Interaction Network
The protein interaction details are taken from STRING v10
Database [23]. STRING provides interaction details of pro-
teins with biomolecules with a confidence score in the inter-
val [0,1] corresponding to every interaction. In this work, a
protein pair is considered to be interacting if their confi-
dence score is 0.3 or above. The organism is restricted to
homo sapiens. The protein interaction matrix MPP is con-
structed as follows:

1; if Sij > 0:3
MPP ði; jÞ ¼ : vital information about functions shared by similar
0; otherwise
Where Sij is the confidence score between Proteini and
Proteinj
2.1.3 LncRNA Co-Expression Network
LncRNA expression data is downloaded from NONCODE
4.0 database [20]. It contains the expression profiles of
90,062 lncRNA transcripts in 24 different cell types. The
Pearson Correlation Coefficient (PCC) between every pair
of lncRNAs is computed to determine the co-expressing
lncRNAs. Let X ¼ fx1 ; . . . ; x24 g and Y ¼ fy1 ; . . .; y24 g are
the expression profiles of lncRNA i and j respectively. Then
the lncRNA correlation matrix PLL is computed as follows:
 
covðX; Y Þ
PLL ði; jÞ ¼  :
sX sY 
Subsequently, the lncRNA adjacency matrix MLL is con-
structed as
 between lncRNA objects and function objects of HLPFN, a
1; if PLL ði; jÞ > 0
MLL ði; jÞ ¼ : meta-path based measure known as AvgSim [15] is used.
0; otherwise
Followed by MLL ði; iÞ ¼ 0, to remove self loops.
2.1.4 LncRNA Function Association Network
The function of lncRNA predicted using lnc-GFP method is
available in NONCODEv4.0. The lnc-GFP set already
includes the functions predicted by Liao Q et al. [9]. It
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257
contains ten functions for 1,961 lncRNA. This data is consid-
ered as the known associations between lncRNAs and func-
tions. The matrix for known lncRNA-function association,
MLF is defined as

1; if LncRNAi has Functionj
MLF ði; jÞ ¼ :
0; otherwise
2.1.5 Protein Function Association Network
The functions associated to proteins is obtained from Uni-
Prot database [24], which consists of the mapping of protein
molecules to 17,073 unique functional GO Terms. The pro-
tein-function association matrix is constructed from this
data by the following equation:

MPF ði; jÞ ¼ :
0; otherwise
HLFPN Construction
The HLPFN is constructed by integrating these sub-net-
works. It has been inferred from recent studies that, most of
the time, lncRNA functions through interactions with pro-
teins. The inclusion of lncRNA-protein interaction network
helps to fetch this information. If an lncRNA li interacts
with a protein pi and if pi interacts with another protein pj ,
then there is a probability for li to interact with protein pj .
The protein-protein interaction sub-network identifies such
relationships. Then lncRNA co-expression network imparts
lncRNAs. The functional association networks of lncRNAs
and proteins are used to enrich the HIN with already
known functions.
The final network (HLPFN), obtained by integrating the
sub-networks, consists of thousands of nodes with dense
interconnections. The network schema of HLPFN is shown
in Fig. 1b. It contains three nodes of type lncRNA (l) func-
tion (f) and protein (p). The link types between protein-pro-
tein and lncRNA-protein are interacts with, the link type
between lncRNA and function is performs or performed by
and the link type between protein and function is also per-
forms or performed by. A portion of the HLPFN developed is
shown in Fig. 2. The numbers of nodes and links of different
types are summarised in Table 1.
2.2 Selection of Relevant Meta-Paths
In any HIN based study, meta-path is an influential parame-
ter which plays a key role in extracting useful information
from the HIN. In this work, to quantify the relatedness
Since AvgSim is a path constrained measure, the selection
of relevant meta-paths is vital. In homogeneous networks
all paths between any pair of objects are semantically alike
and are relatively easy to handle. In contrast, HIN contains
several kinds of paths between any given pair of objects.
Each one of these significantly differ in semantics, even
though they connect the same pair of objects, and demands
meticulous manipulation.
 258 IEEE/ACM TRANSACTIONS ON COMPUTATIONAL BIOLOGY AND BIOINFORMATICS, VOL. 19, NO. 1, JANUARY/FEBRUARY 2022

Fig. 1. Work flow of predicting lncRNA function. a) Heterogeneous lncRNA-protein-function network construction. First the homogeneous networks of
protein-protein interaction, lncRNA co-expression and lncRNA-function association are built from adjacency matrices of protein-protein interaction
data (STRING), lncRNA co-expression data (NONCODE v4.0) and lncRNA-function association data (Gene Ontology). LncRNA-protein interaction
(NPInter 3.0) matrix connects lncRNA co-expression and protein-protein interaction networks. They are connected to functions using known
lncRNA-function association data (NONCODE 4.0) and protein-function association data (Uniprot). (b) The network schema of heterogeneous
lncRNA-protein-function network consisting of three nodes lncRNA, protein, and function and edges connecting them. Meta-paths are generated by
doing depth first search in the network schema with the given path length. (c) Computation Avgsim score along all the meta-paths. (d) The score for
every lncRNA-function pair along different meta-paths is arranged as a row vector and a two-dimensional matrix is constructed by combining these
row vectors. This acts as the feature set to train the random forest classifier.

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 V ET AL.: HETEROGENEOUS INFORMATION NETWORK MODEL FOR LONG NON-CODING RNA FUNCTION PREDICTION
Fig. 2. A section of constructed HLPFN. The rectangles, ellipses and tri-
angles represent lncRNAs, proteins and functions respectively. The
edges between them show association between the nodes.
To demonstrate, consider the meta-paths of length three in
HLPFN: lpf and llf, both connecting an lncRNA object and
function object (for simplicity, the relationship names between
the objects are omitted). The semantics of meta-paths can be
determined by considering the relationships connecting them.
interacts with performs
Meta-path lpf means lncRNA









! protein





!
co  expresses with
function. Whereas, llf means lncRNA













!
performs
lncRNA





! function. The former meta-path corre-
sponds to the functions performed by lncRNA by interacting
with proteins. While the latter example represents a meta-math
with functions shared by co-expressing lncRNAs or similar
lncRNAs.
A relevant meta-path is a meta-path which conveys use-
ful information to solve an HIN based problem at hand. In
most of the cases, relevant meta-paths are suggested by
domain experts based on the peculiarities of the problem
and the input data set. In our problem, the exact knowledge
about the mechanism in which each lncRNA functions is
not known. Therefore, every meta-path in the HLFPN needs
to be considered equally relevant. This assumption necessi-
tates the selection process of relevant meta-paths to be
automated.
The brute-force approach is to consider all the meta-
paths which connects lncRNAs and functions and check for
their validity. This approach is infeasible because the num-
ber of possible meta-paths increases exponentially with the
increase in meta-path length (the number of objects in the
meta-path), making the problem intractable. One solution is
to go ahead with the typical trends found in HIN studies.
Generally in an HIN, it is meaningless to increment the
meta-path length indefinitely. Obviously, in lengthy meta-
paths, the chain of relations connecting starting and ending
objects can be very long. Hence unintelligent incrementa-
tion of meta-path length often proves counterproductive
and yields results with much lesser accuracy [18]. In the
wake of this knowledge, most HIN based techniques set an
upper threshold for meta-path length, in advance. They
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259
TABLE 1
Details of LncRNA-Protein-Function Network
Type Count
Objects lncRNA 2758
protein 8501
function 1416
Links lncRNA-lncRNA 1947266
lncRNA-function 15689
lncRNA-protein 28317
protein-function 13658
protein-protein 58372
consider only the meta-paths shorter than the threshold.
While setting such a threshold, it is important to make sure
that the results are not affected badly due to the removal of
higher length paths. If results are affected, the threshold
value must be reconsidered and this practice rationalises
the fixation of threshold limit. Generally, the threshold limit
can be set randomly, empirically or heuristically.
In this work, an empirical approach is employed. Starting
from length three, the correlation of all lf meta-paths (that start
with lncRNA and end with function) with actually existing lf
associations are estimated iteratively. The point at which the
count of negatively correlated meta-paths equals half of the
positively correlated meta-paths, the iteration stops. The path
length at this point is taken as the length threshold. Ensuing
two paragraphs explain this process in detail.
In the first step, an iterative process on the meta-path
length is performed in which the candidate meta-paths to
be included in the experiment are identified. As the problem
is to find the relatedness between lncRNA and function,
only those meta-paths which start with lncRNA (l) and end
with function (f) are considered. The iteration must start
with the least possible meta-path: lf, of length two. In fact,
this path represents the existing functional association of
lncRNAs and corresponds to direct lf links in the HIN.
Thus in practice, the iteration starts with a meta-path length
of three. In every iteration, a vector is formed with the total
number of meta-paths of that type between every pair of
lncRNAs and functions, called meta-path vector.
The second step is choosing the relevant meta-paths. If
the meta-path under consideration is relevant, then it fol-
lows from network properties that its count between l and f
would be more. This implies that the lncRNA is quite likely
to perform that function. Conversely, if the number of meta-
paths happens to be less, then the probability of the lncRNA
to perform that function is small. In order to quantify this
trend, a correlation analysis of meta-path vector is per-
formed against the known lf association vector. All meta-
paths in the meta-path vector showing positive correlation
with known lf associations are concluded to be relevant
and others to be irrelevant. The terminating criterion is for-
mulated in such a way that the iteration stops when the
count of negatively correlated meta-paths equals half of the
positively correlated meta-paths. As stated already, the iter-
ation starts with a meta-path length of three and repeated
until the terminating condition is met. In this work, the ter-
minating criterion is met at a meta-path length of four,
which is taken as the length threshold.
 260 IEEE/ACM TRANSACTIONS ON COMPUTATIONAL BIOLOGY AND BIOINFORMATICS, VOL. 19, NO. 1, JANUARY/FEBRUARY 2022
Fig. 3. Relevant meta-path selection: Correlation analysis for relevant
meta-path selection with meta-path lengths 3 (dotted curve), 4 (dashed
curve) and 5 (solid curve). The meta-paths lpf and llf have positive cor-
relation with known data set. The meta-paths except lplf of path length
four have positive correlation. Three meta-paths of length five are nega-
tively correlated with known lf associations.
The correlation analysis of meta-path vector of lengths
three, four, and five are shown in Fig. 3. It is clear that in the
third iteration, there exist three negatively correlated paths
among the eight possible meta-paths of length five. Hence
the path length is fixed to be four. Thus, the relevant paths
obtained are: lpf; llf; lllf; llpf and lppf.
2.3 AvgSim
To find relatedness between two objects in HIN, D. Xiao
et al. [15] proposed a measure called AvgSim. AvgSim value
of two objects is the average of reachable probability under
the given meta-path and the reverse path. Given a meta-
path P , then the AvgSim between source object s and target
t is given by
1 obtained as follows:
AvgSimðs; tjP Þ ¼ ½RW ðs; tjP Þ þ RW ðs; tjP 1 Þ:
2 The probabilities assigned by the classifier to each associ-
Where RW ðs; tjP Þ is the Random walk from s to t along the
path P . The equation can be expanded by decomposing the
meta-path P . Assume P is a composition of relations
R1 ; R2 ; . . . ; Rl , then
jOðsjR
X1 Þj
1 score than threshold are True Negatives. False Positives are
RW ðs; tjR1 ; R2 ; . . . ; Rl Þ ¼
jOðsjR1 Þj i¼1
RW ðOi ðsjR1 Þ; tjR2 ; . . . ; Rl Þ

1; if s and t are same
and RW ðs; tÞ ¼ : is further evaluated using statistical metrics such as accu-
0; otherwise
Where jOðsjR1 Þj is the number of out-neighbours of s based
on relation R1 . If there is no out-neighbour for s under R1 ,
then the relatedness value of s and t is 0.
2.4 Details of the Classifier
Let l be the total number of lncRNAs and f be the total num-
ber of functions in the experiment (l = 2,758 and f = 1,416
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from Table 1). The AvgSim score along each relevant meta-
path for every lncRNA-function pair is computed and rep-
resented as an lf matrix. There will be a separate matrix
for each meta-path as shown in Fig. 1c. For any meta-path k,
the entry ði; jÞ of its corresponding matrix represents the
AvgSim score along the meta-path (k) between lncRNA i
and function j. The matrices for all meta-paths are depicted
in Fig. 1c. As explained in Section 2.2, there are five relevant
meta-paths in the experiment. The feature set for the classi-
fier is constructed by deriving another matrix from the indi-
vidual meta-path matrices shown in Fig. 1c. The header
column of this new matrix is the lncRNA-function pairs and
header row is the meta-paths. The entries represent the
AvgSim score between the lncRNA-function pair provided
in the header row for the meta-path provided as the column
header. This matrix is used as the feature set to train the
classifier and has the structure provided in Fig. 1d. There
are two class labels, one representing positive class which
indicates the lncRNA and function are associated and the
other representing the negative class, which indicates the
lncRNA and function are not associated.
The lncRNA-function association data, taken from NON-
CODE repository provided 15,689 positive examples. Ide-
ally, all the non-associated pairs must form negative
examples. In such a scenario, the number of negative exam-
ples would be far more than that of positive examples and
can lead to a skewed training set. To avoid that, we applied
a random sampling on the non-associated pairs and selected
11,835 negative examples and maintained a 57:43 ratio on
positive and negative examples. The classifier is imple-
mented using the Caret [16] package in R language.
2.5 Performance Evaluation Metrics
The prediction performance is validated by k-fold cross-val-
idation. True Positive (TP) and True Negative (TN) repre-
sent the samples which are correctly predicted as positives
and negatives respectively. False Positive (FP) and False
Negative (FN) represent the number of positive and nega-
tive samples which are wrongly predicted. They are
ation is taken as the predictor score for that association. All
pairs are sorted based on the predictor score. Number of
known associations with higher predictor score than spe-
cific threshold score position are True Positives and the
number of unknown associations with a lower predictor
the number of unknown associations with predictor score
above threshold whereas False Negatives are known associ-
ations with a score below the threshold.
By varying the threshold value, Receiver Operating
Characteristics (ROC) curves are drawn. The performance
racy, precision, recall and f-score. Another metric called cov-
erage is used to compare performance with existing
approaches. It is the proportion of lncRNAs annotated with
functions to the total number of lncRNAs considered.
Correctly annotated lncRNAs
Coverage ¼ :
Total lncRNAs
 V ET AL.: HETEROGENEOUS INFORMATION NETWORK MODEL FOR LONG NON-CODING RNA FUNCTION PREDICTION 261

TABLE 2
Performance Measures

Accuracy 73.68% Precision 71.75%

Recall 72.73% F-score 72.23%

RF model showed the best accuracy among the five candi-

date models and hence selected for the experiment.

Fig. 4. Comparison of different classification models.
2.6 Choice of the Classifier
Before performing the actual prediction process, the best
model that suits the input data and yields the best result has
been determined. This is achieved by comparing the per-
formances of different classification models for the selected
data set and experimental set up. The candidate models
were: (a) Artificial Neural Network (ANN), (b) Gradient-
Boosting Machine (GBM), (c) Generalised Linear Models
(GLM) (d) Random Forest (RF) and (e) Support Vector
Machine (SVM). Each model is implemented in R language
with the default parameters and is evaluated using 10-fold
cross-validation. The results are summarised in Fig. 4. The
3 RESULTS
The model predicted new functions for 2,695 lncRNAs with
73.68 percent accuracy. The values of other performance
measures are given in Table 2. Some of the lncRNAs were
predicted to have multiple functions. The function predic-
tion results show that lncRNAs are mostly involved in bio-
logical process rather than cellular functions or molecular
functions. The method was able to predict functions of
many lncRNA which were previously unknown.
The functions are taken from GO consortium. The GO
ontology follows parent-child relationships among them
based on certain functional categories called GOSlim,
GOBasic, etc. Here the functional GO Terms are classified
based on their GOSlim category to understand various
kinds of functions performed by lncRNAs. The category-
wise list is shown in Table 3. The table shows a list of func-
tional categories with the count of GO terms belonging to
that category. It shows that the important functions

TABLE 3
Important Functions of LncRNAs

GO Class ID Definition Count GO Class ID Definition Count

GO:0008150 biological_process 2536 GO:0016301 kinase activity 23
GO:0008152 metabolism 757 GO:0005886 plasma membrane 22
GO:0003674 molecular_function 511 GO:0004871 signal transducer activity 21
GO:0007275 development 362 GO:0007610 behavior 21
GO:0005575 cellular_component 359 GO:0005654 nucleoplasm 19
GO:0016043 cell organization and biogenesis 344 GO:0005102 receptor binding 19
GO:0005623 cell 315 GO:0016032 viral life cycle 19
GO:0007154 cell communication 299 GO:0004672 protein kinase activity 18
GO:0007165 signal transduction 263 GO:0003677 DNA binding 18
GO:0019538 protein metabolism 247 GO:0040029 regulation of gene expression& epigenetic 18
GO:0006810 transport 246 GO:0009607 response to biotic stimulus 17
GO:0009058 biosynthesis 227 GO:0003723 RNA binding 17
GO:0005488 binding 227 GO:0005739 mitochondrion 16
GO:0030154 cell differentiation 194 GO:0030234 enzyme regulator activity 15
GO:0003824 catalytic activity 191 GO:0008233 peptidase activity 14
GO:0006950 response to stress 176 GO:0016049 cell growth 14
GO:0009653 morphogenesis 156 GO:0000166 nucleotide binding 14
GO:0006464 protein modification 155 GO:0008092 cytoskeletal protein binding 13
GO:0006996 organelle organization and biogenesis 149 GO:0008289 lipid binding 11
GO:0005737 cytoplasm 122 GO:0005576 extracellular region 10
GO:0005515 protein binding 122 GO:0005783 endoplasmic reticulum 10
GO:0006629 lipid metabolism 96 GO:0005768 endosome 10
GO:0007049 cell cycle 81 GO:0000228 nuclear chromosome 10
GO:0006811 ion transport 79 GO:0005794 Golgi apparatus 9
GO:0009719 response to endogenous stimulus 75 GO:0005773 vacuole 8
GO:0009605 response to external stimulus 74 GO:0003700 transcription factor activity 7
GO:0016787 hydrolase activity 71 GO:0005764 lysosome 6
GO:0009056 catabolism 71 GO:0004518 nuclease activity 6
GO:0006259 DNA metabolism 69 GO:0005198 structural molecule activity 6
GO:0016740 transferase activity 68 GO:0005730 nucleolus 5
GO:0000003 reproduction 66 GO:0019748 secondary metabolism 4

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 262 IEEE/ACM TRANSACTIONS ON COMPUTATIONAL BIOLOGY AND BIOINFORMATICS, VOL. 19, NO. 1, JANUARY/FEBRUARY 2022

Fig. 5. Performance comparison with the methods of LncRNA2Function

and NeuranetL2GO.

performed by lncRNAs are biological process, metabolism,

development, cellular component and molecular function. Fig. 6. Relative importance of meta-paths in RF.
These results are obtained using the CateGOrizer tool [25].

3.1 Comparison With Other Approaches
A comparison of our model with two state-of-the art mod-
els, LncRNA2Function [13] and NeuraNetL2GO [42] is
done using a separate test set, lncRNA2GO-55, provided for
free download by Zhang et al. in NeuraNetL2GO [42]. The
performance is compared using the metrics of F-score (F),
precision (PRE) and recall (REC) and our model is found to
perform the best. Fig. 5 shows the results of the performance
comparison. In terms of coverage (the ratio of annotated
lncRNAs to total lncRNAs) as well, the proposed method
has shown satisfactory performance (Table 4).
4 DISCUSSION
This section is subdivided into two. In the first part, the vari-
ous measures used in selecting meta-paths are described. In
the second part, the impact of lncRNA co expression sub-
network in the final result is explained.
llpf; lllf (from Section 2.2). The RF classifier ranks the features
based on their importance and leverage in obtaining the final
prediction result. This ranking is graphically displayed in
Fig. 6. The paths lllf; llpf; llf are high ranked. In an experimen-
tal setup with the number of direct lncRNA-protein interac-
tions are limited, the incorporation of meta-path based
approach helped to reveal functions of lncRNA through the
path lllf and llf by incorporating co-expression networks of
lncRNAs.
4.1.2 Justification of Relevant Path Selection
This section justifies the correctness of relevant meta-path
selection process described in Section 2.2. The entire explana-
tion here is based on Fig. 7. It may be recalled from Section 2.2
that the meta-paths lpf, llf, lllf, llpf, lppf were determined to
be relevant and lplf to be irrelevant.

4.1 Measures Taken in Meta-Paths Selection

Here, a discussion on the relative importance of meta-paths
as features for the RF classifier is provided. Further an ana-
lytic confirmation that the paths identified by the relevant
path selection process are truly relevant is furnished. The
final part establishes the correctness in setting the upper
threshold for meta-path length as four.

4.1.1 Relative Importance of Meta-Paths

The various meta-paths within the length threshold that con-
stituted the feature set for the classifier were lpf; llf; lplf; lppf;

TABLE 4
Comparison With Existing Methods for an Fig. 7. Verification of relevant path selection with accuracy. The triangles
Independent Test of 55 lncRNAs represents the accuracy when all paths are considered. Circles repre-
sent the accuracy when the individual paths are removed. Diamonds
Model Annotated Coverage (%) represent the accuracy when a particular path is removed along with
lplf. The accuracy got increased when path lplf was removed indicating
LncRNA2Function 18 32.7 that it is irrelevant. The accuracy is improved when less correlating lpf,
NeuranetL2GO 50 90.9 llf and lppf are removed individually. However, when they are removed
Proposed Model 48 87.3 along with irrelevant lplf the accuracy is decreased. This means that
when only lplf is removed, the prediction performance is enhanced.

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 V ET AL.: HETEROGENEOUS INFORMATION NETWORK MODEL FOR LONG NON-CODING RNA FUNCTION PREDICTION
Fig. 8. ROC curve for prediction results for various meta-path length
thresholds. The dotted line shows ROC curve obtained by meta-path length
threshold as three. It spans lesser area than thresholds of four and five
given in dashed and solid types respectively. The ROC curves of thresholds
four and five are almost overlapping and span nearly equal areas.
The experiment is conducted by including all the paths
up to a length of four and measuring the accuracy. At first,
the irrelevant path suggested by the methodology (lplf) is
removed. The accuracy was improved by this, affirming
that the path as truly irrelevant. This is clear from Fig. 7.
Although, the paths lpf, llf and lppf are positively corre-
lated, they have low correlation coefficient compared to lllf
and llpf (Refer to Fig. 3, in Section 2.2 to note correlation
coefficients). The removal of paths with high correlation
coefficient lllf and llpf drops the accuracy, indicating them
as truly relevant. Whereas, the accuracy is not reduced (in
fact, got improved) when positively correlated meta-paths
with low correlation coefficients (lpf, llf and lppf) are
removed individually. Still they are not concluded to be
truly irrelevant because when each one of them is removed
along with the irrelevant (and already removed) lplf, the
accuracy is affected. This means, these paths cause opposite
effects on accuracy when removing individually and when
removed along with irrelevant and already removed lplf.
Conclusively, lpf, llf, lllf, llpf, lppf are truly relevant and
could not be removed, since lplf is already removed. Hence,
it is proved that the automated selection process of meta-
paths yielded truly relevant/irrelevant meta-paths.
Additionally, the relevant meta-paths selected is signifi-
cant in terms of biological shreds of evidence as well. The
irrelevant meta-path, lplf has the semantics that an lncRNA
interacts with a protein which in turn interacts with an
lncRNA to perform a function. As per the current evidence,
proteins are directly performing functions and their func-
tions are derived very rarely through lncRNAs [1]. Whereas,
the semantic meanings of all the relevant meta-paths deter-
mined as relevant by the automated selection process are
found to be closely related to biologically verified lncRNA-
function mechanisms.
4.1.3 Justification for Upper Threshold on Meta-Path
Length
The upper threshold for meta-path length is fixed to be four as
described in Section 2.2. The overall complexity of the model
is Oðn2 þ mg þ lfm log mÞ, where n is the largest of number
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263
Fig. 9. Effect of lncRNA co-expression data on prediction result. The
solid line is the ROC curve for the experiment when all interactions are
considered. The dashed line represents the experiment with lncRNA co-
expression data is removed.
of lncRNAs/proteins/functions present in the experiment, m
and g represent the number and length of meta-paths respec-
tively, l and f represent the number of lncRNAs and functions
in the experiment. It may be noted that the number and length
of meta-paths included in the experiment (m) play a major
role in determining the overall complexity. Moreover, these
two are the parameters which we have the flexibility to curtail
by selecting or discarding meta-paths according to the length
thresholds fixed in advance.
An ROC curve analysis reveals that this selection is opti-
mum, as the improvement in result for longer meta-paths is
disproportionate to the computational time invested for
processing more number of meta-paths of higher lengths.
The ROC curves for experiments with path lengths three,
four and five is given in Fig. 8. The length four meta-path
experiment shows significantly better performance than
that with three. Whereas, the length five meta-path experi-
ment does not improve the result to an extend which can be
compensated for the additional computational overhead
required to process the meta-paths of length five. Conclu-
sively, the selection of upper threshold for meta-path length
as four is optimal for the selected data set.
4.2 Effect of Inclusion of LncRNA Co-Expression
Data
One of the novelty added in this paper is the incorporation of
lncRNA co-expression data into the network. This informa-
tion helps to identify functionally similar lncRNAs. The co-
expression profiles of lncRNAs in 24 tissues were used to find
the similarity between lncRNAs. Clinical evidence ascertain
that lncRNAs have tissue-specific expression and their loc-
ation greatly affects the function performed by them. There-
fore tissue-specific co-expression details of lncRNAs can
identify functionally related lncRNAs with much better clar-
ity. Considering this fact, it can be concluded that the incorpo-
ration of lncRNA co-expression data has indeed helped to
improve the prediction accuracy. This speculation is justified
with the help of an ROC curve analysis of the function predic-
tion result in a network with and without lncRNA co-expres-
sion data. The analysis is pictorially represented in Fig. 9. It
shows that a consistent drop in AUC has occurred when
lncRNA co-expression network was discarded from the HIN.
 264 IEEE/ACM TRANSACTIONS ON COMPUTATIONAL BIOLOGY AND BIOINFORMATICS, VOL. 19, NO. 1, JANUARY/FEBRUARY 2022

TABLE 5 TABLE 6
Predicted Functions of HOTAIR Predicted Functions of H19

5 CASE STUDY
In order to further demonstrate the predictive performance of
It is the primary example of an RNA expressed on one chromo-
the proposed model, a case study containing two well known
some that has been found to influence transcription of another
lncRNAs is conducted. The lncRNAs selected are HOTAIR
chromosome. The HOTAIR gene contains 6,232 bp and encodes
and H19 with respective NONCODE identifiers NON-
2.2 kb lncRNA molecule. HOTAIR is associated with many dis-
HSAG011264, NONHSAG007409. The case study primarily
eases and its aberrant expression causes the progression of vari-
focuses on the predicted functional association of these two
ous cancers. It is classified as an oncogenic lncRNA.
lncRNAs that are clinically established. However, it covers a
Twenty-five major functions of HOTAIR predicted by the
few of the most prominent functional associations predicted
model are shown in Table 5. The study successfully pre-
by the proposed model, even though they are not experimen-
dicted almost all the function associations of HOTAIR, for
tally validated. These are tagged ‘not reported’ in the respec-
which evidence exist in current literature.
tive tables. The list of ‘not reported’ cases are not exhaustive.

5.1 HOTAIR 5.2 H19

HOX transcript antisense RNA (HOTAIR)[26] is an lncRNA H19 is located in chromosome 11. It plays crucial roles in
located on chromosome 12. It is co-expressed with HOXC genes. diseases like Wilms Tomour 2 and Beckwith-Wiedemann

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 V ET AL.: HETEROGENEOUS INFORMATION NETWORK MODEL FOR LONG NON-CODING RNA FUNCTION PREDICTION
Syndrome and acts as tumour suppressor in some cancers.
It is involved in all stages of tumorigenesis. It has a highly
conserved structure and its function depends on the struc-
ture [33]. H19 is associated with hypertension, coronary
artery disease, atherosclerosis, ischemia, and heart failure.
[34]. Twenty-five important functions of H19, predicted by
the model are summarised in Table 6. It can be observed
that the most important and experimentally proven func-
tion associations of the lncRNA, H19 are predicted success-
fully by the model.
6 CONCLUSION AND FUTURE WORK
Growing evidence for functional roles played by lncRNAs
in biological and cellular activities shaped the contemporary
research issue of fast and efficient functional annotation of
lncRNAs. Since the wet-lab process to functionally annotate
lncRNAs is expensive and tedious, computational alterna-
tives have drawn tremendous research attention these days.
The work proposed here, predicts the lncRNA functions
from their protein interaction data and co-expression
details. While the existing methods mostly concentrate on
protein interaction of lncRNAs for functional annotation,
this method considers lncRNA co-expression similarity and
association with existing functions, in addition to protein
interaction. More importantly, the method associates func-
tions with lncRNAs even if they lack protein interaction.
The study demonstrates that AvgSim applied along meta-
paths can effectively evaluate the relevance of lncRNA-
function pairs in an HIN. The model yielded an overall pre-
diction accuracy of 74 percent.
One possible research direction in future is the incorporation
of more information about lncRNA to the network. LncRNA is
proven to interact with different kinds of biomolecules such as
RNA, miRNA and siRNA. Integration of such interaction
details to the model may enhance the prediction performance.
Accuracy of the results may be further enhanced by the incor-
poration of more number of biological characteristics of
lncRNAs to the model. That apart, the present work uses a cor-
relation-based procedure to set the upper threshold of meta-
path length. Replacement of this approach by a generic and
well-formulated algorithm can make the methodology more
effective. This will indeed benefit all HIN mining tasks using
meta-paths, irrespective of their application domains.
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Adheeba Thahsin received the PG degree in
computer science and engineering from the
Department of Computer Science and Engineer-
ing, National Institute of Technology Calicut, India
in 2018. She currently works for Nokia Networks
Chennai, India. She is interested in bioinformat-
ics, data mining, and networks.
Manju M received the PhD degree in life sciences
from the University of Kerala, India, in 2011. Cur-
rently she is working as an assistant professor
with the Department of Zoology, KSM DB College
Sasthamcotta, Kerala, India since July 2012. Her
research interests include molecular biology, his-
topathology, phytochemistry, and bioinformatics.
Gopakumar G (Member, IEEE) received the PhD
degree in bioinformatics from the University of
Kerala, India, in 2013. Currently he is working as
an assistant professor with the Department of
Computer Science and Engineering, National
Institute of Technology Calicut, India since July
2010. His research interests include RNA bioin-
formatics, biological network analysis, and data
mining. He is a member of the ACM.

Sunil Kumar P V received the PhD degree in

computer science and engineering from the " For more information on this or any other computing topic,
Department of Computer Science and Engineer- please visit our Digital Library at www.computer.org/csdl.
ing, National Institute of Technology Calicut,
India. He is currently working as an associate
professor with the Computer Science Depart-
ment of CMR Institute of Technology, Bangalore,
India. His areas of interests includes computa-
tional biology, bioinformatics, data mining, and
biological networks.

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