Aberrant transcription and post-transcriptional processing of hepatitis C virus non-structural genes in transgenic mice

Mayura M. Desai, Batbayar Tumurbataar, Yueqing Zhang, Lee Nien Lillian Chan, Jiaren Sun, Teh Sheng Chan

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Hepatitis C virus (HCV) infection is a leading cause of chronic liver disease worldwide. Since several aspects of the infection remain unresolved, there is a pressing need for a convenient animal model that can mimic the clinical disease and aid the evaluation of treatment strategies. Although some success has been achieved in transgenic approaches for development of rodent models of HCV, transgenic expression of the complete HCV polyprotein or an entire set of the viral non-structural (NS) proteins continues to be a serious challenge. Using northern blot and 5′ rapid amplification of cDNA ends (RACE), we unraveled two possible mechanisms that can impede HCV NS transgene expression in the mouse liver. Several truncated transcripts are produced from alternate transcription start sites along the HCV NS sequence within the murine environment, in vivo. Translation of these shorter transcripts is blocked either by the positioning of a contextual stop codon or through a shift in the reading frame. In addition, the complete NS transcript undergoes trans-splicing through 5′ recombination with a non-transgene-derived, spliced leader sequence that appends a potential stop codon upstream of the translation start. These findings thus demonstrate that HCV NS-derived transgenes are subject to aberrant transcriptional initiation and post-transcriptional processing in the nucleus of a mouse host. Strategies to prevent such aberrant transcription start/RNA processing might be key to the development of a successful HCV transgenic mouse model.

Original languageEnglish (US)
Pages (from-to)1273-1284
Number of pages12
JournalTransgenic Research
Volume20
Issue number6
DOIs
StatePublished - Dec 2011

Fingerprint

Hepatitis C virus
Hepacivirus
Transgenic Mice
transcription (genetics)
genetically modified organisms
mice
Genes
genes
Terminator Codon
stop codon
Transgenes
translation (genetics)
transgenes
Viral Nonstructural Proteins
Spliced Leader RNA
animal models
Trans-Splicing
trans-splicing
Polyproteins
Reading Frames

Keywords

  • Aberrant transcription
  • Hepatitis C virus
  • Non-structural proteins
  • Trans-splicing
  • Transgenic mouse

ASJC Scopus subject areas

  • Biotechnology
  • Genetics
  • Agronomy and Crop Science
  • Animal Science and Zoology

Cite this

Aberrant transcription and post-transcriptional processing of hepatitis C virus non-structural genes in transgenic mice. / Desai, Mayura M.; Tumurbataar, Batbayar; Zhang, Yueqing; Chan, Lee Nien Lillian; Sun, Jiaren; Chan, Teh Sheng.

In: Transgenic Research, Vol. 20, No. 6, 12.2011, p. 1273-1284.

Research output: Contribution to journalArticle

Desai, Mayura M. ; Tumurbataar, Batbayar ; Zhang, Yueqing ; Chan, Lee Nien Lillian ; Sun, Jiaren ; Chan, Teh Sheng. / Aberrant transcription and post-transcriptional processing of hepatitis C virus non-structural genes in transgenic mice. In: Transgenic Research. 2011 ; Vol. 20, No. 6. pp. 1273-1284.
@article{c27127fcd14742e7ad9f2e67fb90dbb0,
title = "Aberrant transcription and post-transcriptional processing of hepatitis C virus non-structural genes in transgenic mice",
abstract = "Hepatitis C virus (HCV) infection is a leading cause of chronic liver disease worldwide. Since several aspects of the infection remain unresolved, there is a pressing need for a convenient animal model that can mimic the clinical disease and aid the evaluation of treatment strategies. Although some success has been achieved in transgenic approaches for development of rodent models of HCV, transgenic expression of the complete HCV polyprotein or an entire set of the viral non-structural (NS) proteins continues to be a serious challenge. Using northern blot and 5′ rapid amplification of cDNA ends (RACE), we unraveled two possible mechanisms that can impede HCV NS transgene expression in the mouse liver. Several truncated transcripts are produced from alternate transcription start sites along the HCV NS sequence within the murine environment, in vivo. Translation of these shorter transcripts is blocked either by the positioning of a contextual stop codon or through a shift in the reading frame. In addition, the complete NS transcript undergoes trans-splicing through 5′ recombination with a non-transgene-derived, spliced leader sequence that appends a potential stop codon upstream of the translation start. These findings thus demonstrate that HCV NS-derived transgenes are subject to aberrant transcriptional initiation and post-transcriptional processing in the nucleus of a mouse host. Strategies to prevent such aberrant transcription start/RNA processing might be key to the development of a successful HCV transgenic mouse model.",
keywords = "Aberrant transcription, Hepatitis C virus, Non-structural proteins, Trans-splicing, Transgenic mouse",
author = "Desai, {Mayura M.} and Batbayar Tumurbataar and Yueqing Zhang and Chan, {Lee Nien Lillian} and Jiaren Sun and Chan, {Teh Sheng}",
year = "2011",
month = "12",
doi = "10.1007/s11248-011-9494-x",
language = "English (US)",
volume = "20",
pages = "1273--1284",
journal = "Transgenic Research",
issn = "0962-8819",
publisher = "Springer Netherlands",
number = "6",

}

TY - JOUR

T1 - Aberrant transcription and post-transcriptional processing of hepatitis C virus non-structural genes in transgenic mice

AU - Desai, Mayura M.

AU - Tumurbataar, Batbayar

AU - Zhang, Yueqing

AU - Chan, Lee Nien Lillian

AU - Sun, Jiaren

AU - Chan, Teh Sheng

PY - 2011/12

Y1 - 2011/12

N2 - Hepatitis C virus (HCV) infection is a leading cause of chronic liver disease worldwide. Since several aspects of the infection remain unresolved, there is a pressing need for a convenient animal model that can mimic the clinical disease and aid the evaluation of treatment strategies. Although some success has been achieved in transgenic approaches for development of rodent models of HCV, transgenic expression of the complete HCV polyprotein or an entire set of the viral non-structural (NS) proteins continues to be a serious challenge. Using northern blot and 5′ rapid amplification of cDNA ends (RACE), we unraveled two possible mechanisms that can impede HCV NS transgene expression in the mouse liver. Several truncated transcripts are produced from alternate transcription start sites along the HCV NS sequence within the murine environment, in vivo. Translation of these shorter transcripts is blocked either by the positioning of a contextual stop codon or through a shift in the reading frame. In addition, the complete NS transcript undergoes trans-splicing through 5′ recombination with a non-transgene-derived, spliced leader sequence that appends a potential stop codon upstream of the translation start. These findings thus demonstrate that HCV NS-derived transgenes are subject to aberrant transcriptional initiation and post-transcriptional processing in the nucleus of a mouse host. Strategies to prevent such aberrant transcription start/RNA processing might be key to the development of a successful HCV transgenic mouse model.

AB - Hepatitis C virus (HCV) infection is a leading cause of chronic liver disease worldwide. Since several aspects of the infection remain unresolved, there is a pressing need for a convenient animal model that can mimic the clinical disease and aid the evaluation of treatment strategies. Although some success has been achieved in transgenic approaches for development of rodent models of HCV, transgenic expression of the complete HCV polyprotein or an entire set of the viral non-structural (NS) proteins continues to be a serious challenge. Using northern blot and 5′ rapid amplification of cDNA ends (RACE), we unraveled two possible mechanisms that can impede HCV NS transgene expression in the mouse liver. Several truncated transcripts are produced from alternate transcription start sites along the HCV NS sequence within the murine environment, in vivo. Translation of these shorter transcripts is blocked either by the positioning of a contextual stop codon or through a shift in the reading frame. In addition, the complete NS transcript undergoes trans-splicing through 5′ recombination with a non-transgene-derived, spliced leader sequence that appends a potential stop codon upstream of the translation start. These findings thus demonstrate that HCV NS-derived transgenes are subject to aberrant transcriptional initiation and post-transcriptional processing in the nucleus of a mouse host. Strategies to prevent such aberrant transcription start/RNA processing might be key to the development of a successful HCV transgenic mouse model.

KW - Aberrant transcription

KW - Hepatitis C virus

KW - Non-structural proteins

KW - Trans-splicing

KW - Transgenic mouse

UR - http://www.scopus.com/inward/record.url?scp=80855156669&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=80855156669&partnerID=8YFLogxK

U2 - 10.1007/s11248-011-9494-x

DO - 10.1007/s11248-011-9494-x

M3 - Article

VL - 20

SP - 1273

EP - 1284

JO - Transgenic Research

JF - Transgenic Research

SN - 0962-8819

IS - 6

ER -