COMPARATIVE EXPRESSION ANALYSIS
OF HUMAN ENDOGENOUS RETROVIRUS ELEMENTS
IN PERIPHERAL BLOOD OF CHILDREN
WITH SPECIFIC LANGUAGE IMPAIRMENT
Minchev DS1,2,*, Popov NT3, Naimov SI1, Minkov IN4, Vachev TI1
*Corresponding Author: Assistant Professor Danail S. Minchev, Department of Medical Biology,
Faculty of Medicine, Medical University-Plovdiv, 4000, Plovdiv, Bulgaria. Tel: +359-896-313-627.
E-mail: dante17@abv.bg
page: 49
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DISCUSSION
To date, there have been no published data on HERV
expression in the context of the SLI condition. To the
best of our knowledge, this is the first cohort study to
announce differences in transcript abundance of specific
HERV genes in the blood of children with SLI compared
with a control group. We have studied HERV transcript
levels in peripheral blood of children with SLI. Throughout
our study we have analyzed the expression pattern of five
different HERV loci: HERV-K (HLM-2) gag, HERV-K
env, HERV-W pol, HERV-P env and HERV-R env. All
of the five genes studied appeared to be ubiquitously expressed
in the peripheral blood of children in both the SLI
and control groups. Two of these, HERV-K (HLM-2) gag
and HERV-P env, appeared to be differentially expressed
between the two groups.
Despite the growing evidence of a strong genetic basis
for SLI during the last decade, the precise genetic mechanisms
of SLI remain elusive. Many researchers suggest
that SLI is a multi causation condition with both genetic
and environmental factors involved. Numerous molecular
studies have established a set of SLI-associated genes
whose single nucleotide polymorphism (SNP) profile or
differential expression is of particular importance for SLI
development [20]. Despite this large amount of research
effort, no assessment of the HERV expression has been
made in the aforementioned studies.
In some cases, HERV regulatory regions and HERV
encoded products may play an important role in essential
physiological processes. For example, syncytin-1 and
syncytin-2 proteins that mediate trophoblast cell fusion
during placental development, derive from HERV Envelope
proteins. In a recent study, Bhat et al. [21] revealed
that HERV-K Env is able to promote a considerable neuroprotective
effect in a case of HIV infection. According
to Thompson et al. [22], and Sundaram et al. [23], about
20.0% of all functionally active transcription factor binding
sites in human and murine genomes are LTR-related.
We observed relevant changes in gene expression in
terms of a small but statistically significant reduction in
HERV-K (HLM-2) gag (1.41-fold) and HERV-P env (1.67-
fold) transcript levels. The HERV downregulation presumes
an active suppression of these elements. As HERV expression
is modulated by various mechanisms, the differential
gene expression we observed is probably a result of many
factors affecting HERV regulation. Regulation mechanisms
of particular importance involve DNA methylation and
several trans-acting transcription factors [24]. Generally,
transcription of active HERV loci is mediated by a 5’-
LTR core promoter able to support transcription at a basal
level. Transcription is negatively regulated mainly by CpG
methylation at the 5’-LTR. According to Wentzensen et al.
[25], the expression of a specific member of the HERV-H
in gastrointestinal cancer cells correlates with demethylation
of the 5’-LTR. The presence of enhancer sequences
within the 5’-LTRs has also been demonstrated. In addition,
several trans-acting transcriptional factors, which bind to
HERV promoters and en-hancers, have been identified:
YY1, Sp-1, Oct-1, GATA, GCM1 [24,26-28] Nevertheless,
our RNA-seq data from a previous expression study
on pooled SLI and ASD samples [29] suggests no changes
in the expression levels of the aforementioned transcription
factors and the most DNA-methyltransferases. On this
basis, we can speculate that the observed differences in
the HERV transcript levels can be due to negligibly small
but specific changes in various gene regulation processes. Further efforts are still needed for a complete characterization
of HERV regulation.
The most important findings in our study were that
HERV expression levels in blood correlate negatively with
the SLI development and may specifically discriminate
SLI patients from healthy controls. The expression profile
we obtained may be useful for the investigation of many
diseases of the central nervous system that are suspected
to be associated with the retroviral activity.
While the patient cohort was very well characterized
and representative for an SLI population, the total number
of participants was not large enough to definitively create
a model for prediction of SLI or characterize HERV
expression differences that may be more highly associated
with SLI subtypes. Due to the small sample size, analysis
of the data with respect to medication, sex, special diet,
race, ethnicity or other potential confounding covariates,
was not conclusive.
Our findings are in agreement with several other
studies in which HERV downregulation has been clearly
established [30-33]. Alterations in HERV expression occur
in various pathological conditions, in a wide variety of
cancer conditions, in inflammation reactions, and in autoimmunity
[30-33]. While a remarkable number of studies
support the overexpression of HERVs in various complex
conditions, our findings are entirely coherent with those
in which significantly lower expression levels of specific
HERV loci has also been reported [30-36].
In spite of the fact that a vast majority of human endogenous
retrovirus elements are upregulated in malignant
cells, in a very few cancer cases, their expression is suppressed.
Syncytin-1 is described to be underexpressed in
several tumor types, which suggest its potential beneficial
effect. Syncytin-1 has been shown to be downregulated
in pancreatic adenocarcinomas, while its stable expression
in a melanoma cell line correlates with restricted
cell growth [30].
Liang et al. [31] evaluated transcription of the HERVrelated
gene psiTPTE22-HERV in kidney, liver, lung, and
stomach tumors in comparison with normal tissue samples.
The authors prove that psiTPTE22-HERV transcripts were
notably lower in all tumor tissues examined. Their results
confirm that the expression of the HERV-related gene is
suppressed solely in the cancer samples and that this suppression
correlates with the malignancy of the cells [31].
According to Kowalczyk et al. [32], HERV-W env
expression in peripheral blood mononuclear cell (PBMC)
samples from patients with localized scleroderma, negatively
correlates with the severity of the disease. Moreover,
HERV-W env levels in skin samples from the patients
were distinctively lower, compared to those in the control
group samples [32].
Lattekivi et al. [33] performed a differential expression
study of HERVs in psoriasis at a whole transcriptome
level. The authors observed high expression of repetitive
elements in both patients and healthy controls. Most of
the endogenous retrovirus loci with significant changes
in expression between the two studied groups appeared
to be downregulated in psoriasis skin. The authors set a
differential expression fold change thresholds at 0.71 and
1.41 and a false discovery rate at <0.01. They discovered
downregulation of 17 HERV families in lesional and three
HERV families in non-lesional psoriatic skin in comparison
with healthy skin. Their findings clearly demonstrated
the global repression of the endogenous retrovirus elements
in psoriatic skin. The HERV downregulation has
also been confirmed in psoriasis by Gupta et al. [34].
Weis et al. [35] discovered a substantial reduction in
the HERV-W gag gene expression levels in brain samples
from patients with schizophrenia and bipolar disorder.
Along with a noticeable overexpression of HERV-H, Balestrieri
et al. [36] discovered downregulation of HERV-W
in peripheral blood samples of children with autistic spectrum
disorder. In contrast to HERV-H, HERV-W was found
to be downregulated in the autistic group compared to the
healthy controls (with less than a 2-fold change). These
results clearly suggest that HERV transcript levels can
specifically characterize a complex psychiatric condition
such as autism and serve as putative molecular markers for
it. It is noteworthy to mention that despite the small absolute
change, the reported HERV-W downregulation is still
considered important in terms of statistical significance.
Our results together with the vast scientific data obtained
by other research groups support that HERV genes
play an important role in normal cell processes. Human
endogenous retroviruses are not only “junk” or “selfish”
DNA, but also the key factors and markers for many pathological
conditions. Further clarification of the molecular
mechanisms and pathways in which HERVs participate is
needed for a complete understanding of their functions in
norm and pathology.
In general, despite the huge body of evidence supporting
overexpression of HERVs in many diseases, pathologies
with significantly lower expression levels of HERVs
have also been reported [30-36]. In this context, our study
presents evidence of minor (>1.4-fold), but statistically
reliable downregulation of two HERV-encoded genes.
Our finding is consistent with previous studies in which
low HERV expression has been described. Of particular
interest is the fact that differential expression of HERV-K
(HML-2) gag and HERV-P env is a sensitive marker that
can discriminate children with SLI from healthy controls.
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