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Studies on Human Endogenous Retroviruses (HERVs) with Special Focus on ERV3
Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
2002 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Human endogenous retroviruses (HERVs) represent approximately 7% of the human genome. This investigation was focused on one particular HERV, ERV3, with the main purpose of characterising its gene expression patterns and genomic distribution of ERV3-like sequences. Furthermore, this careful expression study should provide insights into the biological role of HERVs. The impact of HERVs in health and disease is not yet clarified. ERV3 is expressed as three envelope (env) transcripts, of which two also contain a cellular gene, H-plk (human proviral linked Krüppel). ERV3 env expression was mainly investigated at the RNA level. The gene expression of two other HERVs, HERV-K and HERV-E was analysed and compared with ERV3 activity.

Real-time PCRs were developed and in combination with in situ hybridisation, it was found that ERV3 is expressed in a tissue- and cell-specific way. High levels of ERV3 mRNA (up to six times over Histone3.3) were demonstrated in placenta, sebaceous glands, foetal and adult adrenal glands, brown adipose tissue, corpus luteum, pituitary gland, thymus and testis. In monocytic cells including both normal monocytes and malignant U-937 cells, elevated mRNA levels were observed after retinoic acid (RA)-induced differentiation. ERV3-encoded Env protein was detected in selected cases, one following RA-treatment. In addition, several new ERV3-like sequences were discovered in the human genome.

ERV3 was found to have conserved open reading frames in contrast to other ERV3-like sequences in the human genome. This suggests that ERV3 may be involved in important cellular processes such as differentiation, cell fusion, immunomodulation and protection against infectious retroviruses. The developed techniques and obtained results will allow further studies of HERV expression to better correlate HERV activity to both normal development and disease.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis , 2002. , p. 61
Series
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 0282-7476 ; 1165
Keyword [en]
Genetics, human endogenous retroviruses, HERV, ERV3, expression, in situ hybridisation, real-time PCR, U-937, retinoic acid.
Keyword [sv]
Genetik
National Category
Medical Genetics
Research subject
Pathology
Identifiers
URN: urn:nbn:se:uu:diva-2097ISBN: 91-554-5342-2 (print)OAI: oai:DiVA.org:uu-2097DiVA, id: diva2:161745
Public defence
2002-06-01, Rudbecksalen, Uppsala, 09:15
Opponent
Available from: 2002-05-10 Created: 2002-05-10 Last updated: 2018-01-13Bibliographically approved
List of papers
1. Elevated levels of the human endogenous retrovirus ERV3 in human sebaceous glands
Open this publication in new window or tab >>Elevated levels of the human endogenous retrovirus ERV3 in human sebaceous glands
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1996 (English)In: Journal of Investigative Dermatology, ISSN 0022-202X, E-ISSN 1523-1747, Vol. 106, no 1, p. 125-128Article in journal (Refereed) Published
Abstract [en]

ERV3 (HERV-R) is a complete human endogenous retrovirus located on the long arm of chromosome 7. Long terminal repeat-envelope (env) gene spliced mRNAs of 9 and 3.5 kb are widely expressed in human tissues and cells, but gag-pol mRNAs have not been found. Furthermore, the env gp70 gene contains an open reading frame throughout its length. The highest expression of ERV3 mRNA detected so far is in placenta and the lowest in choriocarcinoma cell lines. We have previously shown that the human monoblastic cell line U-937 and some normal and neoplastic tissues also express high levels of ERV3 env message by Northern blot analysis; however, this method does not distinguish between mRNA expression in different cell types in tissues. In this report, we have studied the ERV3 mRNA expression in specific cell types of human skin by in situ hybridization. We found high levels expression of ERV3 env mRNA in human sebaceous glands in normal skin and dermoid cysts of the ovary. In all glands, the expression is maximal in the periphery of the lobule and ceases towards the center in the region of characteristic holocrine secretion. Since it is known that the regulation of sebaceous glands is primarily via steroid hormones, particularly androgens, it is possible that expression of ERV3 is hormone dependent.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-89897 (URN)10.1111/1523-1747.ep12329612 (DOI)8592062 (PubMedID)
Available from: 2002-05-10 Created: 2002-05-10 Last updated: 2017-12-14Bibliographically approved
2. Expression of the endogenous retrovirus ERV3 (HERV-R) during induced monocytic differentiation in the U-937 cell line
Open this publication in new window or tab >>Expression of the endogenous retrovirus ERV3 (HERV-R) during induced monocytic differentiation in the U-937 cell line
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1996 (English)In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 67, no 3, p. 451-456Article in journal (Refereed) Published
Abstract [en]

ERV3 (HERV-R) is a complete human endogenous retrovirus located on the long arm of chromosome 7. LTR-env-gene-spliced mRNA of 9 and 3.5 Kb is widely expressed in human tissues and cells, but gag-pol mRNA has not been found. Further, the env gp70 gene contains an open reading frame throughout its length and its expression has recently been detected as a full-length protein. The highest expression of ERV3 detected so far is in placenta and the lowest in cytotrophoblasts and choriocarcinoma cell lines. In this report we have studied ERV3 mRNA and protein expression in the human monoblastic cell line U-937 during differentiation into monocytes/macrophages. Differentiation of U-937 cells was induced by 1,25a-dihydroxyvitamin D3 (vitD3), retinoic acid (RA), gamma interferon (IFN-gamma) and phorbol-myristate-acetate (PMA-TPA). The expression of ERV3 env mRNA was found to be differentiation-associated, with high expression detected in the late stages of monocytic development. Using TPA, the expression of ERV3 env was detected as 9- and 3.5-kb transcripts by Northern blotting, as mRNA by in situ hybridization and as a cytoplasmic 65-kDa protein by immunofluorescence and Western blots. Low levels of basal expression were found, with up-regulation of both message and protein at 24 to 48 hr after addition of TPA. Induction with vitD3, IFN-gamma and RA produced higher levels of mRNA at earlier time points. It is concluded that the U-937 cell line represents an excellent model system for further studies to study the relationship between ERV3 expression and cellular differentiation.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-89898 (URN)10.1002/(SICI)1097-0215(19960729)67:3<451::AID-IJC23>3.0.CO;2-9 (DOI)8707424 (PubMedID)
Available from: 2002-05-10 Created: 2002-05-10 Last updated: 2017-12-14Bibliographically approved
3. Developmnental expression of HERV-R (ERV3) and HERV-K in human tissue
Open this publication in new window or tab >>Developmnental expression of HERV-R (ERV3) and HERV-K in human tissue
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2002 (English)In: Virology, ISSN 0042-6822, E-ISSN 1096-0341, Vol. 297, no 2, p. 220-225Article in journal (Refereed) Published
Abstract [en]

The human endogenous retroviruses (HERVs), ERV3 (HERV-R) and HERV-K, are both known to be transcriptionally active in human placenta. In the case of ERV3 there is also indirect evidence for its participation in cellular differentiation. In this study we examined the expression of ERV3 (HERV-R) and HERV-K in human normal fetal tissues by in situ hybridization. The highest level of ERV3 env expression was detected in primitive adrenal cortex. Elevated levels of expression were also found in the following developing tissues: kidneys (tubules), tongue, heart, liver, and central nervous system. Tissue-specific expression was found for HERV-K rec (former cORF) but not for pol/int transcripts. The highest rec expression was found in placenta and levels slightly higher than sense control were found in the rest of the tissues examined. Pol/Int was not possible to quantitate. It appears that ERV3 is expressed in an organ-specific way during embryogenesis and might suggest a possible role in the development and differentiation of human tissues.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-89899 (URN)10.1006/viro.2002.1428 (DOI)12083821 (PubMedID)
Available from: 2002-05-10 Created: 2002-05-10 Last updated: 2017-12-14Bibliographically approved
4. ERV3 and related sequences in humans; studies of RNA expression by real-time PCR and in situ hybridisation
Open this publication in new window or tab >>ERV3 and related sequences in humans; studies of RNA expression by real-time PCR and in situ hybridisation
Manuscript (Other academic)
Identifiers
urn:nbn:se:uu:diva-89900 (URN)
Available from: 2002-05-10 Created: 2002-05-10 Last updated: 2010-01-13Bibliographically approved
5. ERV3 in relation to cell differentiation in normal and neoplastic monocytes
Open this publication in new window or tab >>ERV3 in relation to cell differentiation in normal and neoplastic monocytes
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Manuscript (Other academic)
Identifiers
urn:nbn:se:uu:diva-89901 (URN)
Available from: 2002-05-10 Created: 2002-05-10 Last updated: 2010-01-13Bibliographically approved

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