ISSN 0006-2979, Biochemistry (Moscow), 2025, Vol. 90, No. 11, pp. 1566-1583 © Pleiades Publishing, Ltd., 2025.
Russian Text © The Author(s), 2025, published in Biokhimiya, 2025, Vol. 90, No. 11, pp. 1670-1688.
1566
REVIEW
Long Non-Coding RNA JPX:
Structure, Functions, and Role in Chromatin Architecture
Arseniy V. Selivanovskiy
1,2,3#
, Anastasiia L. Sivkina
1#
, Sergei V. Ulianov
1,2
,
and Sergei V. Razin
1,2,a
*
1
Institute of Gene Biology, Russian Academy of Sciences, 119334 Moscow, Russia
2
Moscow Institute of Physics and Technology, 141700 Dolgoprudny, Russia
3
Faculty of Biology, Lomonosov Moscow State University, 119234 Moscow, Russia
a
e-mail: sergey.v.razin@inbox.ru
Received August 20, 2025
Revised November 7, 2025
Accepted November 8, 2025
Abstract— Long non-coding RNAs (lncRNAs) are a novel class of regulators of key cellular processes and
biomarkers of various pathologies. The lncRNA JPX is a multifunctional RNA involved in the regulation of
transcription, translation, and chromatin architecture. JPX influences transcription and enhancer-promoter
communication by regulating binding of proteins to DNA, particularly by interacting with the chromatin
architectural protein CTCF. Additionally, JPX can interact with microRNAs, repressor proteins, or mRNA sta-
bilizers, regulating translation in pathogenesis of oncological and other diseases. This review summarizes the
accumulated knowledge about the structure, evolutionary origin, and functions of the long non-coding RNA
JPX in normal and pathological conditions.
DOI: 10.1134/S0006297925602692
Keywords: lncRNA, JPX, transcription regulation, translation regulation, gene expression regulation, X chromo-
some inactivation, chromatin
* To whom correspondence should be addressed.
# These authors contributed equally to this study.
INTRODUCTION
Although the protein-coding exons constitute
only about 1.5% of the genome, more than 75% of
the genome is transcribed, including non-coding RNAs
(ncRNAs) [1]. Initially, ncRNAs were identified as RNAs
lacking an apparent open reading frame and were
considered to be mere byproducts of transcription.
However, hundreds of long non-coding RNAs (lncRNAs)
essential for cell survival have since been identified
[2]. Traditionally, lncRNAs are defined as ncRNAs lon-
ger than 200 nucleotides [3], but according to a new-
er classification, lncRNAs are ncRNAs longer than 500
nucleotides [4, 5]. Most lncRNAs are characterized by
relatively low expression levels (with notable excep-
tions such as NEAT1 or MALAT1 [6, 7]), tissue specific-
ity, low evolutionary conservation, and the presence of
isoforms resulting from alternative splicing [5, 8-10].
The recently accumulated experimental data have
expanded our understanding of lncRNAs as important
regulators of cellular processes. For example, lncRNAs
can facilitate recruitment or displacement of the tran-
scription factors, chromatin remodeling complexes,
and transcription repressors from chromatin [11-15].
Additionally, lncRNAs are involved in establishing the
specific spatial structure of chromatin, which directly
affects gene expression in eukaryotes. In mammalian
cells, genome topology is largely determined by ar-
chitectural proteins such as cohesin and CTCF, whose
binding can be regulated by specific lncRNAs [16-18].
lncRNAs can regulate chromatin architecture at dif-
ferent levels – from loops to the structure of entire
chromosomal territories. This is achieved through
the rich protein interactome of these molecules [19-
21]. For example, during X chromosome inactivation
(XCI), the lncRNA Xist recruits transcription repressors
(such as SPEN) and architectural proteins (such as
SMCHD1) and displaces RNA polymerase II, cohesin,
JPX lncRNA 1567
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and CTCF [22]. All these interactions contribute to
chromatin restructuring at the chromosomal level
and overall inactivation of transcription on the X
chromosome.
Moreover, the transcribed lncRNA genes can act
as enhancers of transcription for other genes, form-
ing spatial contacts with them [23-25]. In some cas-
es, knockdown of the lncRNAs themselves does not
affect expression of the regulated genes, unlike the
inhibition of transcription or deletion of structural el-
ements of lncRNA genes [3, 4]. In this case, lncRNAs
may be mere “byproducts” of the act of transcription,
which itself plays a regulatory role. Such hypothesis
has been proposed in the literature for a number of
enhancer RNAs [3]. However, it is worth noting that at
least sometimes, lncRNAs transcribed from enhancers
are involved in establishing enhancer–promoter con-
tact and transcription regulation [4]. In general, de-
spite the differences in stability and modifications of
such enhancer-associated lncRNAs and “typical” en-
hancer RNAs (many of which apparently do not have
any functions), a clear division of these RNA classes
is currently absent [4].
lncRNAs also regulate expression at the transla-
tion level, for example, by binding to the 5′ end of
the target RNA and recruiting polysomes [26, 27], or
by directly binding to mRNA, increasing their stabil-
ity. Finally, lncRNAs can bind microRNAs (miRNAs),
preventing their access to mRNA and thus promoting
translation of the latter [28-30]. One lncRNA can bind
several miRNAs, simultaneously acting as a regulator
of many biochemical pathways [31].
The lncRNA JPX (just proximal to XIST, primate
lncRNA) is an example of a multifunctional RNA in-
volved in regulation of transcription, translation, and
chromatin architecture. Initially, its role in X chromo-
some inactivation was discovered, but later its func-
tional repertoire was significantly expanded. In par-
ticular, it has been shown that, at least in certain cell
types, this RNA determines chromatin conformation
and controls cell development programs through in-
teraction with the architectural protein CTCF. In addi-
tion, JPX can directly activate many genes by recruit-
ing transcription activators or displacing repressors.
Finally, through interaction with many proteins and
miRNAs, JPX influences onset and progression of doz-
ens of different pathologies.
STRUCTURE AND EVOLUTIONARY
ORIGIN OF THE JPX GENE
The JPX gene (human Ensembl ID: ENSG0000022547,
NCBI ID: 554203; house mouse Mus musculus Ensembl
ID: ENSMUSG00000097571, NCBI ID: 70252) is located on
the X chromosome and is the closest to the XIST gene
(separated from it by ~10 kb in mice and ~90 kb in
humans) [32, 33] (Fig. 1). Other names of the JPX
gene include ENOX (expressed neighbor of XIST),
LINC00183, DCBALD06, or NCRNA00183 in humans
and Enox, 2010000I03Rik, or 2510040I06Rik in house
mice. In both mice and humans, this gene is tran-
scribed to form multiple isoforms produced by al-
ternative splicing. Discovered independently by two
research groups, this gene was annotated both as a
three-exon variant with polyadenylation signal after
the third exon [32] and as a five-exon variant with
two alternative polyadenylation signals in the region
of the 3′ end of the fifth exon [33]. The predicted exon
positions coincide with those in the RefSeq database;
in humans, the main isoform is 1692 nucleotides long,
consisting of five exons (Fig. 1b). In humans and mice,
this lncRNA is expressed from both the active and
inactive X chromosomes, as demonstrated in various
human tissues [34] (Fig. 2). Like other lncRNA genes
in the X chromosome inactivation center (XIC), the
JPX gene in placental mammals has originated from
a protein-coding gene [35, 36] (Fig. 2).
To date, 124 isoforms of JPX and 100 isoforms
of Jpx (rodent lncRNA) have been annotated in the
Ensembl database based on the MGI sequencing data.
However, contribution of the vast majority of these re-
mains unstudied. The NCBI RefSeq database contains
only one experimentally validated isoform of JPX
(highlighted in red in Fig.2) and Jpx. Nevertheless, the
publicly available RNA-seq data indicate expression of
the alternative JPX isoforms in many tissues (Fig. 2,
human example). It should also be noted that in the
studies where JPX/Jpx knockdown was performed, an-
tisense oligonucleotides and primers for expression
level verification were generally selected for the ex-
ons present in dozens of isoforms [37-39]. Because of
this, it was impossible to determine the physiological
role (and the expression level) of individual isoforms.
To improve understanding of the role of specific iso-
forms, more research is needed, including overexpres-
sion or knockdown of individual isoforms.
Both initial studies identified an extended unmet-
hylated CpG island near the exon 1 of Jpx and showed
gene expression in many mouse tissues [32, 33]. The
gene was found to be conserved in mice, humans, and
cattle, with exon 1 being the most conserved (Fig. 3).
Additionally, the exons 2 and 3 were likely derived
from the mobile genetic elements (MGEs) [32].
Formation of pseudogenes from the protein-cod-
ing genes played a crucial role in the emergence of all
ncRNAs in the XIC of the common ancestor of placen-
tal mammals [40]. XIC is involved in the mechanism
of random X chromosome inactivation, in which ei-
ther the paternal or maternal X chromosome could be
inactivated. The relative arrangement of genes within
the XIC locus is conserved, although the gene sizes,
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Fig. 1. Structure and evolutionary origin of the JPX gene. a) Location of the inactivation center on the human X chromo-
some. b)Exon-intron structure of the JPX isoform ENST00000602772.5. Exons are indicated by rectangles, introns by dashed
lines. c)Genomic organization and comparison of the X chromosome inactivation center region in different species: Gallus
gallus – chicken; Monodelphis domestica – gray short-tailed opossum; Mus musculus – house mouse; Homo sapiens – hu-
man. Non-coding genes localized within the XIC originated from protein-coding genes: XIST, JPX, and FTX from Lnx3, Uspl,
and Wasf3, respectively (adapted from [35, 36], with modifications based on NCBI and UCSC databases).
distances between them, or transcription orientation
have repeatedly changed during evolution due to in-
sertion of MGEs [35] (Fig. 1c).
In particular, the ancestor of the JPX gene is the
ubiquitin-specific protease gene Uspl, which is func-
tional in marsupials [40] (Fig. 1c). The first exon of
JPX originated from the first exon of Uspl, the second
exon of JPX from the fifth exon of Uspl, and one of
the alternative exons of JPX transcripts from the sev-
enth exon [36]. The first exon of JPX is conserved in
mice and humans and generally exhibits the highest
evolutionary conservation (Fig. 3).
Interestingly, the ribosome profiling data indicate
intense ribosome binding in the first exon containing
a short open reading frame (sORF) and translation of
the first exon in various human and mouse tissues
[41]. The region around this frame is highly con-
served among the placental mammals and vertebrates
in general [36, 41]. The functions of sORF include reg-
ulation of transcription and translation. Although the
5′ end of JPX (containing the promoter and the first
two exons) can efficiently initiate transcription of the
luciferase gene when cloned into an expression con-
struct as a promoter, mutation in the start codon of
sORF reduces mRNA production [41]. A similar effect
of this mutation is observed on transcription of the
JPX gene in the endogenous context. Despite the fact
that the mutation in the start codon of the sORF reduc-
es transcription, it nevertheless promotes production
of luciferase, enhancing translation of its mRNA [41].
JPX lncRNA 1569
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Fig. 2. Some isoforms of the lncRNA JPX and its expression profile in various human tissues, according to the Genotype-
Tissue Expression Project (GTEx). Visualization was performed in the UCSC Genome Browser (https://genome.ucsc.edu/).
The only isoform present in the NCBI RefSeq database as a validated transcript is highlighted in red (https://www.ncbi.
nlm.nih.gov/nuccore/NR_024582.1). Purple highlights isoforms from the GENCODE v48 database with exons corresponding
to the regions of active expression, according to GTEx.
This indicates that the wild-type sORF suppresses
translation of the subsequent ORF of luciferase. One
of the mechanisms of this suppression could be com-
petition for ribosome binding. However, these obser-
vations, made in model experiments, do not answer
whether translation of the sORF JPX is important for
realization of the function of this RNA.
Excluding the first exon, the JPX sequence is not
conserved even among placental mammals [42]. This
is explained by the fact that most of JPX arose through
insertion of the MGEs in a species-specific manner [35,
41, 42]. For example, in mice, the exons 2 and 3 have
pronounced homology with the MGEs of the LTR/MaTR
class, while in cattle these two exons demonstrate the
homology with SINE and LINE, respectively. In hu-
mans, the third exon arose from the integration of
SINE [32]. The fourth and fifth exons of the mouse Jpx
gene have pronounced homology with the exons 2-7
of the protein-coding gene Ebag9 and may have aris-
en through retrotransposition [33]. Insertion of MGEs
has also determined the species-specific arrangement
of the genes. For example, in humans, the JPX gene
overlaps with the FTX gene, which is transcribed
in the opposite direction, while in mice, these genes
do not overlap. Most of the region between the 5′ end
of the mouse Jpx gene and the last exon of Ftx is
absent in humans and is represented by the species-
specific MGEs of the SINE and LTR classes [42].
Structural and functional conservation of tran-
scripts of the mouse Jpx gene and the human JPX
gene was investigated in a recent study [43]. It was
shown that the human lncRNA JPX tends to evolve in
a different direction than the lncRNA Jpx in rats and
mice, potentially acquiring new functions. Despite the
abundance of stem-loop structures, mouse and human
RNAs do not have pronounced similarity in the sec-
ondary structure, and their overall spatial structure
differs significantly (Fig. 4). However, it was shown
that expression of a fragment containing the first
three exons of the lncRNA JPX or Jpx in trans com-
pensates for the effect of deletion of the mouse Jpx
gene and increases survival of the mouse cells [43].
Thus, the JPX gene produces multiple transcript
isoforms, is poorly conserved, and emerged through
two mechanisms: pseudogenization of the protein-cod-
ing genes and insertion of MGEs.
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Fig. 3. Alignment of the first exon sequence of Jpx from different mammalian species. a) Comparison of the sequences of
this exon in humans (Homo sapiens), mice (Mus musculus), and cattle (Bos taurus). Regions of complete sequence identity
are shown in yellow, and regions of partial identity are shown in blue. b) Comparison of the sequence of this exon in
mice and humans. Regions of identity (60%) are highlighted in yellow. Alignments were performed using the CLUSTALW
program (https://www.genome.jp/tools-bin/clustalw).
JPX-MEDIATED ACTIVATION
OF XIST DIFFERS
AMONG PLACENTAL ORDERS
The JPX-mediated activation of XIST is best stud-
ied in the orders Rodentia and Primates. The mecha-
nisms of this activation appear to vary both between
and within these orders.
In humans, the JPX gene is located near the XIST
gene and forms a spatial contact with it, acting as a
strong enhancer that transfers RNA polymerase II to
the XIST promoter (regulation in cis) [44]. Transcrip-
tion of the JPX locus is necessary to maintain XIST
transcription in human cells after XCI, while mature,
spliced JPX transcripts are not required for XIST ex-
pression. Thus, in humans, XIST activation is regulat-
ed by transcription of the JPX gene (Fig. 4a).
In the phylogenetically distant common marmo-
set (Callithrix jacchus), the JPX gene does not play an
obvious role in the activation of the XIST gene and
does not form a spatial contact with it [45]. In the
more closely related rhesus macaque (Macaca mulat-
ta), the JPX gene is already involved in the activa-
tion of XIST, although the main role in this process
is played by the macaque-specific enhancer [45]. Ap-
parently, in the order Primates, the activator role of
JPX is strengthened during evolution.
In the order Rodentia, the function of the Jpx
gene has been studied in mice and voles. Interest-
ingly, in the order Rodentia, the expression pattern
of Jpx differs, which could indicate different mecha-
nisms of activation of the Xist gene. For example, in
voles, unlike in mice, the Jpx gene is expressed only
from the active X chromosome [46], is not spliced,
and is transcribed as a single exon of 1.5-2kb [46, 47].
Such a transcript is present only in voles and has no
homologs in other studied rodent species [47]. Finally,
the Jpx gene in voles is transcribed equally efficiently
in both directions [46, 47]. Despite the listed differ-
ences in Jpx expression between mice and voles, the
exact mechanisms of Xist regulation in voles require
clarification.
In mice, the mechanism of lncRNA Jpx-mediat-
ed regulation of the Xist gene is well studied. Unlike
in humans, in mice, transcription of Xist is activat-
ed by the lncRNA Jpx, not by its gene (regulation
intrans) [48] (Fig. 4b). Knockout of Jpx in the female
embryonic stem cells negatively affects expression of
Xist and XCI, impairing differentiation [48]. The effect
of knockout is reproduced by the Jpx knockdown and
is compensated by its ectopic expression [48]. In addi-
tion, the efficiency of XCI is proportional to the level
of expression of the Jpx transgene [49, 50].
A possible explanation for the difference in the
mechanisms of XCI initiation between mice and hu-
mans may be found in the chromatin organization of
this locus, particularly in the different linear distance
between the JPX gene and the XIST promoter [44].
JPX lncRNA 1571
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Fig. 4. Regulation of XIST/Xist gene transcription in humans and mice. a) In humans, the actively transcribed JPX gene acts
as an enhancer, supplying the RNA polymerase II to the XIST gene. The transcript of JPX is not important for the activa-
tion of XIST. b) In mice, the Jpx transcript itself plays a key role. Thus, in humans, the XIST gene is activated by the JPX
gene in cis, while in mice, Xist is activated by the Jpx transcript in trans (based on [4], with modifications). c) Secondary
structure of the fragment of human lncRNA JPX (isoform ENST00000602772.5). The image was obtained using the RNA-
fold Webserver online service (http://rna.tbi.univie.ac.at/cgi-bin/RNAWebSuite/RNAfold.cgi). d) Secondary structure of the
fragment of mouse lncRNA Jpx (isoform ENSMUST00000181020.11). The image was obtained using the RNAfold Webserver
online service (http://rna.tbi.univie.ac.at/cgi-bin/RNAWebSuite/RNAfold.cgi).
SELIVANOVSKIY et al.1572
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In mice, Jpx activates Xist by displacing from its
promoter the CTCF protein, a key and multifaceted
regulator of transcription and chromatin architecture
[49]. However, it should be noted that at least in the
mouse cells, Jpx is able to interact with CTCF beyond
the X chromosome.
Jpx REGULATES CTCF BINDING
ON THE X CHROMOSOME
AND BEYOND
The CTCF protein is considered the main architec-
tural protein of chromatin in vertebrates and exhibits
high conservation among Bilateria. CTCF consists of
unstructured terminal regions and a centrally locat-
ed cluster of 11 C2H2-type zinc fingers; five of these
fingers specifically bind to the CTCF binding motif,
which is conserved among mammals [51-53]. Knock-
out of the Ctcf gene leads to early embryonic lethality
in mice [54-56], indicating the critical importance of
this protein for cellular differentiation and embryonic
development.
Tens of thousands of CTCF binding sites are locat-
ed throughout the genome. Acting as a barrier to DNA
loop extrusion, CTCF serves as a key moderator of
enhancer–promoter communication. On the one hand,
by binding near enhancers and promoters, CTCF could
facilitate formation of the regulatory chromatin con-
tacts. On the other hand, CTCF acts as an insulator
capable of limiting enhancer action and preventing
aberrant activation of transcription. For this reason,
for some genes, CTCF binding in the promoter region
promotes transcription activation, while for others, it
promotes transcription repression [57, 58]. CTCF has
at least three RNA-binding domains, and its ability to
participate in loop formation depends on these do-
mains [59, 60].
In mice, CTCF represses Xist expression by bind-
ing to its promoter region during the XCI. The mouse
lncRNA Jpx promotes Xist activation by reducing
CTCF levels at the promoter by approximately two-
fold during differentiation [49]. The results of RNA
immunoprecipitation (RIP) indicate direct interaction
between CTCF and Jpx, with the first three exons
of Jpx playing a key role in the CTCF binding [37,
49]. A model has been proposed in which Xist ac-
tivation is determined by the ratio of Jpx and CTCF
molecules in the nucleus [49]. In the male cells, which
have a single allele of the lncRNA Jpx gene, its con-
centration is insufficient to prevent CTCF binding,
which is expressed from the two autosomal alleles.
At the same time, in the female cells, both CTCF
and Jpx are expressed from two alleles, allowing
Jpx to displace CTCF from the Xist promoter, initiat-
ing XCI [49].
Jpx is able to bind to CTCF and regulate gene ex-
pression beyond the X chromosome. For example, af-
ter induction of development in the mouse embryonic
stem cells, Jpx begins to bind to chromatin throughout
the genome, displacing CTCF predominantly from the
weak CTCF binding sites at the promoters and en-
hancers of the genes involved in differentiation [37]
(Fig. 5). This Jpx-mediated dissociation of CTCF from
the weak binding sites leads to the redistribution of
cohesin, enhancer–promoter contacts, and changes in
the gene expression profile. This also occurs when
Jpx binds to the CTCF binding site in the Xist pro-
moter. Knockdown of Jpx restores the CTCF-depen-
dent spatial contact between the Xist promoter and
Ftx, characteristic of undifferentiated embryonic stem
cells.
The regulatory role of Jpx is not limited to embry-
onic development. In the hepatocytes isolated from
the starved adult mice, the level of CTCF association
with chromatin is diminished by twofold, despite
the increased level of Ctcf gene expression [61]. This
decrease is especially evident among the promoters
of genes induced under starvation conditions. These
include, for example, genes of carbohydrate and lip-
id anabolism [61]. The observed decrease can be re-
versed by knockdown of Jpx RNA, whose gene also
increases expression in the mouse hepatocytes during
starvation [61].
In contrast to mice, the effect of human lncRNA
JPX on CTCF binding to chromatin is less studied. The
first three exons of human JPX are able to bind CTCF
invitro, and its ectopic expression in the mouse cells
can partially rescue the effect of Jpx knockout [43].
However, presence of JPX interaction with CTCF in
the living cells remains questionable. In particular,
there are conflicting data regarding displacement of
CTCF from the XIST promoter. On the one hand, JPX,
secreted by the hepatocellular carcinoma cells in exo-
somes, can approximately halve the CTCF binding lev-
els at the Xist promoter and intensify transcription of
the luciferase gene under the Xist promoter in HeLa
cells transfected with this construct [62]. On the other
hand, in the human embryonic stem cells, knockdown
of JPX does not increase the level of CTCF binding at
the XIST promoter [44]. The question of the ability of
JPX to regulate CTCF binding on human autosomes
requires further study. However, in addition to CTCF,
JPX can mediate interactions of many other human
proteins with chromatin.
OTHER PROTEIN PARTNERS OF JPX
In addition to CTCF, the protein partners of JPX
in the regulation of gene expression include several
transcription activators and repressors.
JPX lncRNA 1573
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Fig. 5. Regulation of CTCF binding by lncRNA Jpx. In mouse cells, lncRNA Jpx binds CTCF and promotes its dissociation
from the weak binding sites. The strong binding sites retain the ability to bind CTCF. Dissociation of CTCF leads to local
genome restructuring (adapted from Oh et al. [37], with modifications).
For example, in the human smooth muscle cells,
the lncRNA JPX regulates immune response by acti-
vating transcription of the interferon cascade genes
[63]. Expression of the immune genes positively cor-
relates with the JPX expression, which binds in their
promoter regions. The RIP results showed that JPX
directly interacts with the BRD4 and p65 proteins,
which are key regulators of these genes. Knockdown
of JPX significantly reduces binding of BRD4 and p65
to the interferon response genes [63]. These data sug-
gest that JPX forms a complex with p65 and BRD4
and recruits them to the immune response genes.
In addition, JPX is involved in the recruitment
of the SWI/SNF chromatin remodeling complex BRG1.
This remodeler binds to hundreds of tissue-specific
enhancers and maintains chromatin in an “open”
state [64, 65]. In the cultures of human endothelial
cells HUVEC, knockdown of JPX significantly reduces
the level of BRG1 at enhancers and, accordingly, their
activity [38]. Thus, JPX can activate transcription by
recruiting key coactivators and chromatin remodeling
complexes.
Furthermore, JPX can activate genes by prevent-
ing their binding to the repressive Polycomb complex-
es (PRC1 and PRC2). In the human cardiomyocytes, the
EZH2 subunit (H3K27 methyltransferase) of the PRC2
complex co-immunoprecipitates with JPX [66]. Knock-
down of JPX increases the EZH2 recruitment and the
level of the H3K27me3 mark (histone H3 methylated
at position K27) at the promoter of the SERCA2A gene.
This gene is actively expressed in cardiomyocytes and
is necessary to maintain Ca
2+
ion concentration in the
cytosol [66]. An increase in the Ca
2+
concentration fol-
lowing JPX knockdown leads to apoptosis. Thus, JPX
promotes cell survival by derepressing vital genes.
In cytoplasm, JPX also regulates gene expression
at the translational level in at least three ways: by
destabilizing translation repressor proteins, regulat-
ing chemical modifications of mRNA, and interacting
with miRNAs.
For example, adenine methylation at position N6
is recognized by the YTHDF2 protein, which causes
degradation of BMP2 mRNA in the human skin mel-
anoma cells [67]. By directly interacting with YTHDF2
and destabilizing it, JPX increases synthesis of the
BMP2 protein, which is necessary for cell prolifera-
tion [67]. The level of YTHDF2 is regulated through
proteasomal degradation, from which it is protected
by the deubiquitinating protease USP10. Binding of
the YTHDF2 protein to JPX prevents it from interact-
ing with USP10, which ultimately promotes proteol-
ysis of YTHDF2 and synthesis of the BMP2 protein.
In addition, JPX promotes demethylation of N6-
methyladenine in the mRNA of phosphoinositide-
dependent kinase-1 (PDK1), which is necessary for
aerobic glycolysis – the main source of energy in
glioblastoma multiforme cells [68]. In these cells, JPX
binds to the alpha-ketoglutarate-dependent RNA de-
methylase FTO and recruits it to the PDK1 mRNA.
Knockdown of JPX negatively affects demethylation
of PDK1 mRNA and its interaction with FTO, which
negatively affects survival of the glioblastoma multi-
forme cells [68].
In summary, JPX regulates the binding of pro-
teins to chromatin, thereby affecting enhancer-pro-
moter communication and transcription, and inter-
acts with repressor proteins, regulating transcription,
or with mRNA-stabilizing proteins, regulating transla-
tion (Fig. 6). JPX also interacts with miRNAs, thereby
regulating key signaling cascades in various human
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Fig. 6. Mechanisms of gene expression regulation mediated by lncRNA JPX (hJPX) in humans.
cell types. This aspect of JPX biology is of particular
interest, as modulation of signaling cascades is often
associated with the development of pathologies.
JPX AND miRNAs IN NORMAL
PHYSIOLOGY AND PATHOLOGY
miRNAs are a group of small non-coding RNAs
with a wide range of functions. miRNAs bind to the
3′-UTR of mRNAs, thereby stimulating their degrada-
tion or blocking their binding to ribosomes [69, 70].
lncRNAs can complementarily bind miRNAs and in-
hibit their action (competing endogenous RNAs, or
“miRNA sponges”) [71-73]. Acting as a “miRNA sponge,”
JPX enhances translation of the regulated mRNAs.
The expression level of JPX is elevated in many
types of cancer cells [74], and its artificial overexpres-
sion stimulates proliferation of tumor cultures [39, 75,
76] and growth of xenografts in vivo [77-79] (Table1).
The expression level of JPX negatively correlates with
the expression level of some miRNAs, whose ability
to interact with JPX is confirmed by the RIP data with
antibodies against the AGO2 protein [77, 78, 80]. Act-
ing as a “sponge” for miRNAs, JPX increases expres-
sion of oncogenes [81-83]. Knockdown of JPX leads to
the significant decrease in survival and proliferative
activity of tumor cells both in vitro and in mouse
models in vivo [74, 77, 84]. The effects of knockdown
can be partially reproduced using synthetic inhibitors
of JPX and neutralized using synthetic inhibitors of
those miRNAs that interact with JPX [78, 80, 84].
There are also examples of non-oncological dis-
eases where JPX functions as a competing endog-
enous RNA in pathogenesis or disease prevention.
For example, in a healthy individual, JPX facilitates
the survival of nucleus pulposus cells of interverte-
bral discs by binding miR-18a-5p and thus maintain-
ing the level of the HIF-1α protein [85]. Pathological
reduction of HIF-1α levels makes human nucleus pul-
posus cells (HNPC) susceptible to hypoxia and leads
to the intervertebral disc degeneration; the original
state can be restored by overexpressing JPX [85]. Sim-
ilarly, increasing the expression level of JPX promotes
the survival of cardiomyocytes in the ischemia-reper-
fusion syndrome, where JPX binds miR-146b and in-
creases the level of the anti-apoptotic protein BAG-1
[86]. Another example is osteoarthritis, characterized
by massive apoptosis of chondrocytes due to inflam-
matory processes. In chondrocytes, under the influ-
ence of the inflammatory mediator interleukin-1β,
the expression level of JPX increases, which binds the
miR-25-3p. The target of miR-25-3p in chondrocytes is
the mRNA of peptidyl-prolyl isomerase PPID, whose
overexpression mediated by the miR-25-3p inactiva-
tion stimulates chondrocyte apoptosis [87]. An addi-
tional example is allergic rhinitis, where overexpres-
sion of JPX in the CD4
+
cells can disrupt the balance
between the progeny of these cells and be one of
the causes of this disease. By binding miR-378g, JPX
increases the level of CCL5, which leads to an im-
balance between the populations of Treg and Th17
lymphocytes, differentiating from CD4
+
[88].
Thus, by interacting with different miRNAs in
populations of various cells, the lncRNA JPX could be
an important participant in the processes occurring
in many types of cancer and other diseases.
CONCLUSION
lncRNAs are key regulators of cellular process-
es in normal and pathological conditions. The range
of processes regulated by the lncRNA JPX includes
JPX lncRNA 1575
BIOCHEMISTRY (Moscow) Vol. 90 No. 11 2025
Table 1. Role of lncRNA JPX in oncological diseases
Disease Cellular material
Role
of JPX
in pathology
development
Effect of JPX
knockdown
on cells
Regulatory
axis
Methods
Effect
of JPX invivo
(on mouse
xenografts)
References
Endometrial
carcinoma
material from 32 patients
with endometrial cancer;
cultures of Ishikawa, JEC,
HEC-1A, HEC-1B, RL95-2,
AN3 CA, hEEC endometrial
carcinoma cells
promotes inhibits
proliferation
miR-140-3p/
PIK3CA
RIP, luciferase
test, treatment
of cells with JPX
and miR-140-3p
inhibitors,
knockdown
of JPX and PI3KC,
overexpression
of PI3KC
– [39]
Intervertebral
disc
degradation
HNPC (human nucleus
pulposus cells)
prevents – miR-18a-5p/
HIF-1α/
Hippo-YAP
pathway
RIP, luciferase
test, treatment
of cells with JPX
and miR-18a-5p
inhibitors,
knockdown ofHIF-
1α
– [85]
Lung cancer healthy bronchial epithelium
(BEAS-2B) and lung
adenocarcinoma cells
(SPC-A-1, LTEP-a-2, A549,
NCI-H1299)
promotes reduces survival
and proliferation;
decreases Twist1
level
JPX/
miR-33a-5p/
Twist1
luciferase test,
overexpression
of JPX and
miR-33a-5p
overexpression
of JPX promotes
tumor growth
and metastasis
[74]
Head and neck
squamous cell
carcinoma
CAL27 (human head
and neck squamous cell
carcinoma cells);
tumor samples
from 12patients
promotes reduces survival
and proliferation;
stimulates
expression
of miR-193b-3p
and inhibits
expression of PLAU
miR-193b-3p/
PLAU
knockdown of JPX,
overexpression
of JPX and
miR-193b
– [75]
Non-small cell
lung cancer
55 samples from patients;
cultures of non-small
cell lung cancer cells A549,
H1299, H292, H460, SPCA-1,
healthy bronchial epithelial
cells 16HBE
promotes reduces
proliferation,
but does not affect
apoptosis
miR-145-5p/
CCND2
RIP, luciferase test,
treatment of cells
with miR-145-5p
inhibitor
knockdown
of JPX significantly
reduced xenograft
size
[77]
SELIVANOVSKIY et al.1576
BIOCHEMISTRY (Moscow) Vol. 90 No. 11 2025
Table 1 (cont.)
Disease Cellular material
Role
of JPX
in pathology
development
Effect of JPX
knockdown
on cells
Regulatory
axis
Methods
Effect
of JPX invivo
(on mouse
xenografts)
References
Gastric cancer tumor samples
from 32 patients;
cultures of gastric cancer
cells NCI-N87 and MKN-45
and healthy gastric
mucosal cells GES-1
promotes reduces survival
and migration,
increases miR-197
level
miR-197/
CXCR6
Beclin1 luciferase test,
knockdown of JPX,
overexpression
of Beclin 1,
CXCR6 and miR-197
mimics
–
Oral squamous
cell carcinoma
cultures of oral squamous
cell carcinoma cells
(SCC-15, SCC-25, HSC-2,
SCC-9) and healthy oral
keratinocytes (NOK)
promotes reduces survival,
migration, and
proliferation,
stimulates apoptosis
miR-944/
CDH2
RIP, luciferase test,
overexpression
of CDH2
and miR-944,
treatment of cells
with miR-944
inhibitor
– [80]
Breast cancer tumor samples
and adjacent tissues
from 39 patients
promotes reduces survival,
migration, and
proliferation,
stimulates apoptosis
miR-25-3p/
SOX4
RIP, luciferase test,
overexpression
of JPX, CDH2
and miR-25-3p,
treatment of cells
with miR-945
inhibitor
knockdown
of JPX significantly
reduced the size
and growth rate
of xenografts.
The effect
could be reversed
with a miR-945
inhibitor
[78]
Allergic
rhinitis
CD4
+
cell samples
from healthy
individuals and patients
with allergicrhinitis
promotes reduces survival,
migration, and
proliferation,
stimulates apoptosis
miR-378g/
CCL5
RIP, luciferase test,
overexpression
of JPX, CDH2
and miR-25-3p,
treatment of cells
with miR-946
inhibitor
– [88]
Osteoarthritis tissue samples
from 20 patients
with osteoarthritis
and 16 healthy individuals;
chondrocyte culture C28/I2
promotes protects
chondrocytes
from IL-β-induced
damage
miR-25-3p/
PPID
RIP, luciferase test,
overexpression
of PPID, treatment
of cells with
miR-25-3p inhibitor
– [87]
JPX lncRNA 1577
BIOCHEMISTRY (Moscow) Vol. 90 No. 11 2025
Table 1 (cont.)
Disease Cellular material
Role
of JPX
in pathology
development
Effect of JPX
knockdown
on cells
Regulatory
axis
Methods
Effect
of JPX invivo
(on mouse
xenografts)
References
Osteosarcoma tumor samples
and adjacent tissues
from 20 patients;
cultures of hFOB1.19
cells (healthy osteoblast
model), SAOS-2 and U2OS
(osteosarcoma models)
promotes reduces migration
and proliferation of
osteosarcoma cells
miR-33a-5p/
PNMA1
RIP, luciferase test,
overexpression
of miR-33a-5p,
treatment of cells
with miR-33a-5p
inhibitor
– [84]
Esophageal
squamous cell
carcinoma
tumor samples
and adjacent tissues
from 21 patients;
cultures of healthy
esophageal epithelium
Het-1A and esophageal
squamous cell
carcinoma cells (KYSE150,
KYSE450, Eca109,
EC9706)
promotes reduces
proliferation
of esophageal
squamous cell
carcinoma cells
miR-516b-5p/
VEGFA
RIP, luciferase test,
overexpression
of miR-516b-5p
and JPX
knockdown
of JPX significantly
reduced the size
and growth rate
of xenografts, while
overexpression
of JPX had
the opposite effect
[79]
Apoptosis of
cardiomyocytes
during
ischemia-
reperfusion
HL-1 cardiomyocytes prevents – miR-146b luciferase test,
knockdown
of JPX,
inhibition of JPX,
overexpression
of JPX
– [86]
Lung cancer human A549 cells
(lung adenocarcinoma)
as a culture and
as 3D spheroids
promotes – miR-378a-3p/
GLUT1|NRP1|
YY1|Wnt5a
luciferase test,
overexpression
of JPX
– [83]
Note. Based on the data from [82, 83].
SELIVANOVSKIY et al.1578
BIOCHEMISTRY (Moscow) Vol. 90 No. 11 2025
enhancer-promoter communication, transcription,
translation, and many key signaling cascades.
In mouse cells, Jpx affects chromatin architecture
by displacing CTCF from DNA. Although human JPX
is also able to bind CTCF invitro, the question of the
ability of this RNA to interact with CTCF in vivo and
regulate chromatin architecture remains open. Com-
parative studies are needed to clarify the role of Jpx
in the regulation of chromatin architecture in other
placental mammals.
In addition to CTCF, in human cells, JPX regu-
lates the binding of many proteins to chromatin. This
allows it to influence transcriptional programs and
regulate the course of various pathologies. In the fu-
ture, it would be interesting to analyze the effect of
different isoforms of this lncRNA on interactions with
proteins, including CTCF. In addition, the mechanisms
of recruitment of JPX itself to the regulated genes
also remain unstudied.
Current data suggest that JPX is not only a funda-
mental element in maintaining cellular homeostasis
but also a promising target for the therapy of various
diseases. In oncology, JPX is considered a potential
biomarker and target for molecular tools [62, 89-96]
aimed at inhibiting its interactions with miRNAs to
reduce tumor cell proliferation. In non-oncological
pathologies, JPX can be used to correct disorders in
the expression of key proteins involved in cell sur-
vival and function. To develop appropriate strate-
gies, more in vivo experiments are needed to con-
firm the results obtained in cell cultures. In addition,
although JPX appears to be a promising regulator
of non-oncological diseases, the question of chang-
es in its expression level in such diseases remains
open [85, 87].
In conclusion, studies of JPX and other lncRNAs
open new horizons in understanding molecular
mechanisms of genome regulation. JPX serves as an
example of how the non-coding RNAs could integrate
signals at different levels, becoming key players in
the pathogenesis of diseases and promising therapeu-
tic targets. Further study of JPX will not only deepen
our understanding of fundamental processes of cel-
lular regulation but also could help to develop new
approaches to diagnosis and therapy of a wide range
of pathologies.
Abbreviations
lncRNA long non-coding RNA
MGE mobile genetic elements
JPX just proximal to XIST, primate lncRNA
Jpx rodent lncRNA
RIP RNA immunoprecipitation
sORF short open reading frame
XCI X chromosome inactivation
XIC X chromosome inactivation center
Contributions
A. V. Selivanovskiy – literature analysis, writing and
editing the article text; A. L. Sivkina – problem for-
mulation, writing and editing the article text, figure
preparation; S. V. Ulianov – editing the article text;
S. V. Razin – editing the article text.
Funding
This work was financially supported by the Ministry
of Science and Higher Education of the Russian Feder-
ation (agreement no.075-15-2024-539).
Ethics approval and consent to participate
This work does not contain any studies involving hu-
man and animal subjects.
Conflict of interest
The authors of this work declare that they have
noconflicts of interest.
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