Investigation of Human Endogenous Retrovirus-K (ERVK) Expression and Function in Normal Placentation and Preterm Pregnancy

Background: There is a growing body of evidence indicating the importance of endogenous retrovirus (ERV) derived proteins during early development and reproduction in mammals. Recently, a protein derived from the youngest ERV in humans, ERVK (HML2), was shown to be expressed during human placentation. Since a number of highly similar ERVK proviral loci exist across the human genome, locus-specific analysis of ERVK transcription and identification of the coding sequence expressed in the human placenta is difficult. Thus, despite its activity in early human development, the native expression and function of ERVK in the human placenta remains largely uncharacterized. Results: In this study, we comprehensively examined locus-specific ERVK transcription across several human placental tissues and cell types. Through a combination of RNA-seq and siRNA knock-down analyses, we identified the expression of a single ERVK locus, ERVK11q23.3, as (1) being significantly upregulated in preterm compared to term placenta, (2) predominantly expressed by mononuclear trophoblasts, (3) capable of encoding a truncated viral-like envelope protein, and (4) contributing to the expression cytokines involved in both antiviral and anti-inflammatory innate immune responses in human placental trophoblasts and BeWo choriocarcinoma cells, respectively. Conclusions: Collectively, the results of this study highlight the utility of studying locus-specific ERVK expression, provide a thorough characterization of locus-specific ERVK transcription from human placental tissues, and indicate that altered expression of placental ERVK11q23.3 influences interferon antiviral response, which may contribute to preterm birth and other pregnancy complications.

Download Full-text

Human Endogenous Retroviral Long Terminal Repeat Sequences as Cell Type-Specific Promoters in Retroviral Vectors

Journal of Virology ◽

10.1128/jvi.00858-09 ◽

2009 ◽

Vol 83 (23) ◽

pp. 12643-12650 ◽

Cited By ~ 13

Author(s):

Ulrike Schön ◽

Olivia Diem ◽

Laura Leitner ◽

Walter H. Günzburg ◽

Dixie L. Mager ◽

...

Keyword(s):

Transcriptional Control ◽

Leukemia Virus ◽

Cell Types ◽

Retroviral Vectors ◽

Endogenous Retrovirus ◽

Human Endogenous Retrovirus ◽

Cell Type ◽

Specific Expression ◽

Hybrid Vectors ◽

Cell Type Specific

ABSTRACT The human genome contains more than half a million human endogenous retrovirus (HERV) long terminal repeats (LTRs) that can be regarded as mobile regulatory modules. Many of these HERV LTRs have been recruited during evolution as transcriptional control elements for cellular gene expression. We have cloned LTR sequences from two HERV families, HERV-H and HERV-L, differing widely in their activity and tissue specificity into a murine leukemia virus (MLV)-based promoter conversion vector (ProCon). Various human cell lines were infected with the HERV-MLV hybrid vectors, and cell type-specific expression of the reporter gene was compared with the promoter specificity of the corresponding HERV LTRs in transient-transfection assays. Transcription start site analysis of HERV-MLV hybrid vectors revealed preferential use of the HERV promoter initiation site. Our data show that HERV LTRs function in the context of retroviral vectors in certain cell types and have the potential to be useful as cell type-specific promoters in vector construction.

Download Full-text

Human endogenous retrovirus K (HERV-K) is expressed in villous and extravillous cytotrophoblast cells of the human placenta

Journal of Reproductive Immunology ◽

10.1016/j.jri.2011.06.102 ◽

2011 ◽

Cited By ~ 7

Author(s):

U. Kämmerer ◽

A. Germeyer ◽

S. Stengel ◽

M. Kapp ◽

J. Denner

Keyword(s):

Human Placenta ◽

Endogenous Retrovirus ◽

Human Endogenous Retrovirus ◽

Cytotrophoblast Cells ◽

Extravillous Cytotrophoblast

Download Full-text

Modeling of Artificial 3D Human Placenta

Cells Tissues Organs ◽

10.1159/000511571 ◽

2021 ◽

pp. 1-10

Author(s):

Rumeysa Tutar ◽

Betül Çelebi-Saltik

Keyword(s):

Human Placenta ◽

Placental Transfer ◽

Complex Structure ◽

Cell Types ◽

Structure And Function ◽

Technological Advances ◽

And Function ◽

Different Cell Types ◽

Pregnancy And Birth

The placenta is the main organ that allows the fertilized oocyte to develop and mature. It allows the fetus to grow in the prenatal period by transferring oxygen and nutrients between the mother and the fetus. It acts as a basic endocrine organ which creates the physiological changes related to pregnancy and birth in the mother. Removal of wastes and carbon dioxide from the fetus is also achieved by the placenta. It prevents the rejection of the fetus and protects the fetus from harmful effects. Research on the human placenta focuses on understanding the placental structure and function to illuminate the complex structure of this important organ with technological advances. The structure and function of the placental barrier have been investigated with in vitro studies in 2D/3D, and various results have been published comparatively. In this review, we introduce the nature of the placenta with its 3D composition which has been called niche. Different cell types and placental structures are presented. We describe the systems and approaches used in the creation of current 3D placenta, placental transfer models as 3D placental barriers, and micro-engineered 3D placenta on-a-chip to explore complicated placental responses to nanoparticle exposure.

Download Full-text

Primate-restricted KRAB zinc finger proteins and target retrotransposons control gene expression in human neurons

10.1101/856005 ◽

2019 ◽

Author(s):

Priscilla Turelli ◽

Christopher Playfoot ◽

Dephine Grun ◽

Charlène Raclot ◽

Julien Pontis ◽

...

Keyword(s):

Zinc Finger ◽

Embryonic Stem ◽

Zinc Finger Proteins ◽

Endogenous Retrovirus ◽

Adult Brain ◽

Human Endogenous Retrovirus ◽

Regulatory Sequences ◽

Human Neurons ◽

And Function ◽

Transcription Networks

AbstractIn the first days of embryogenesis, transposable element-embedded regulatory sequences (TEeRS) are silenced by Kruppel-associated box (KRAB)-zinc finger proteins (KZFPs). Many TEeRS are subsequently coopted in transcription networks, but how KZFPs influence this process is largely unknown. We identify ZNF417 and ZNF587 as primate-specific KZFPs repressing HERVK (human endogenous retrovirus K) and SVA (SINE-VNTR-Alu) integrants in human embryonic stem cells (ESC). Expressed in specific regions of the human developing and adult brain, ZNF417/587 keep controlling TEeRS in ESC-derived neurons and brain organoids, secondarily influencing the differentiation and neurotransmission profile of neurons and preventing the induction of neurotoxic retroviral proteins and an interferon-like response. Thus, evolutionarily recent KZFPs and their TE targets partner up to influence human neuronal differentiation and physiology.One Sentence SummaryYoung transposable elements and their protein controllers team up to regulate the differentiation and function of human neurons.

Download Full-text

O-glycan recognition and function in mice and human cancers

Biochemical Journal ◽

10.1042/bcj20180103 ◽

2020 ◽

Vol 477 (8) ◽

pp. 1541-1564 ◽

Cited By ~ 2

Author(s):

Gabrielle E. Cervoni ◽

Jane J. Cheng ◽

Kathryn A. Stackhouse ◽

Jamie Heimburg-Molinaro ◽

Richard D. Cummings

Keyword(s):

Tumor Cells ◽

Tumor Development ◽

Cell Types ◽

Protein Glycosylation ◽

Ca 125 ◽

Post Translational Modification ◽

Tn Antigen ◽

Altered Expression ◽

Sialyl Tn Antigen ◽

And Function

Protein glycosylation represents a nearly ubiquitous post-translational modification, and altered glycosylation can result in clinically significant pathological consequences. Here we focus on O-glycosylation in tumor cells of mice and humans. O-glycans are those linked to serine and threonine (Ser/Thr) residues via N-acetylgalactosamine (GalNAc), which are oligosaccharides that occur widely in glycoproteins, such as those expressed on the surfaces and in secretions of all cell types. The structure and expression of O-glycans are dependent on the cell type and disease state of the cells. There is a great interest in O-glycosylation of tumor cells, as they typically express many altered types of O-glycans compared with untransformed cells. Such altered expression of glycans, quantitatively and/or qualitatively on different glycoproteins, is used as circulating tumor biomarkers, such as CA19-9 and CA-125. Other tumor-associated carbohydrate antigens (TACAs), such as the Tn antigen and sialyl-Tn antigen (STn), are truncated O-glycans commonly expressed by carcinomas on multiple glycoproteins; they contribute to tumor development and serve as potential biomarkers for tumor presence and stage, both in immunohistochemistry and in serum diagnostics. Here we discuss O-glycosylation in murine and human cells with a focus on colorectal, breast, and pancreatic cancers, centering on the structure, function and recognition of O-glycans. There are enormous opportunities to exploit our knowledge of O-glycosylation in tumor cells to develop new diagnostics and therapeutics.

Download Full-text

Physical and Functional Interactions of Human Endogenous Retrovirus Proteins Np9 and Rec with the Promyelocytic Leukemia Zinc Finger Protein

Journal of Virology ◽

10.1128/jvi.02771-06 ◽

2007 ◽

Vol 81 (11) ◽

pp. 5607-5616 ◽

Cited By ~ 78

Author(s):

Miriam Denne ◽

Marlies Sauter ◽

Vivienne Armbruester ◽

Jonathan D. Licht ◽

Klaus Roemer ◽

...

Keyword(s):

Germ Cell ◽

Zinc Finger ◽

Transcriptional Repression ◽

Zinc Finger Protein ◽

Germ Cell Tumors ◽

Endogenous Retrovirus ◽

Promyelocytic Leukemia ◽

Human Endogenous Retrovirus ◽

Promyelocytic Leukemia Zinc Finger ◽

Altered Expression

ABSTRACT Only few of the human endogenous retrovirus (HERV) sequences in the human genome can produce proteins. We have previously reported that (i) patients with germ cell tumors often make antibodies against proteins encoded by HERV-K elements, (ii) expression of the HERV-K rec gene in transgenic mice can interfere with germ cell development and induce carcinoma in situ, and (iii) HERV-K np9 transcript is overproduced in many tumors including breast cancers. Here we document that both Np9 and Rec physically and functionally interact with the promyelocytic leukemia zinc finger (PLZF) tumor suppressor, a transcriptional repressor and chromatin remodeler implicated in cancer and the self-renewal of spermatogonial stem cells. Interaction is mediated via two different central and C-terminal domains of Np9 and Rec and the C-terminal zinc fingers of PLZF. One major target of PLZF is the c-myc proto-oncogene. Coexpression of Np9 and Rec with PLZF abrogates the transcriptional repression of the c-myc gene promoter by PLZF and results in c-Myc overproduction, altered expression of c-Myc-regulated genes, and corresponding effects on cell proliferation and survival. Thus, the human endogenous retrovirus proteins Np9 and Rec may act oncogenically by derepressing c-myc through the inhibition of PLZF.

Download Full-text

Role of the 807 C/T Polymorphism of the α2 Gene in Platelet GP Ia Collagen Receptor Expression and Function

Thrombosis and Haemostasis ◽

10.1055/s-0037-1614605 ◽

1999 ◽

Vol 81 (06) ◽

pp. 951-956 ◽

Cited By ~ 59

Author(s):

J. Corral ◽

R. González-Conejero ◽

J. Rivera ◽

F. Ortuño ◽

P. Aparicio ◽

...

Keyword(s):

Venous Thrombosis ◽

Cell Types ◽

Receptor Expression ◽

Case Control Studies ◽

Platelet Surface ◽

Vitro Analysis ◽

And Function ◽

In Vitro Analysis

SummaryThe variability of the platelet GP Ia/IIa density has been associated with the 807 C/T polymorphism (Phe 224) of the GP Ia gene in American Caucasian population. We have investigated the genotype and allelic frequencies of this polymorphism in Spanish Caucasians. The T allele was found in 35% of the 284 blood donors analyzed. We confirmed in 159 healthy subjects a significant association between the 807 C/T polymorphism and the platelet GP Ia density. The T allele correlated with high number of GP Ia molecules on platelet surface. In addition, we observed a similar association of this polymorphism with the expression of this protein in other blood cell types. The platelet responsiveness to collagen was determined by “in vitro” analysis of the platelet activation and aggregation response. We found no significant differences in these functional platelet parameters according to the 807 C/T genotype. Finally, results from 3 case/control studies involving 302 consecutive patients (101 with coronary heart disease, 104 with cerebrovascular disease and 97 with deep venous thrombosis) determined that the 807 C/T polymorphism of the GP Ia gene does not represent a risk factor for arterial or venous thrombosis.

Download Full-text