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Nucleic Acids Research 2004 32(17):5019-5028; doi:10.1093/nar/gkh821
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Published online 24 September 2004

Nucleic Acids Research, Vol. 32 No. 17 © Oxford University Press 2004; all rights reserved

Lsh, an epigenetic guardian of repetitive elements

Jiaqiang Huang, Tao Fan, Qingsheng Yan, Heming Zhu, Stephen Fox1, Haleem J. Issaq1, Lionel Best2, Lisa Gangi2, David Munroe2 and Kathrin Muegge*

Laboratory of Molecular Immunoregulation, SAIC-Basic Research Program, 1 Laboratory of Proteomics and Analytical Technologies and 2 Laboratory of Molecular Technology, SAIC-Frederick, National Cancer Institute, Frederick, MD 21701, USA

* To whom correspondence should be addressed at LMI, SAIC, National Cancer Institute, BLDG 469, Room 243, Frederick, MD 21701, USA. Tel: +1 301 846 1386; Fax: +1 301 846 7077; Email: muegge{at}ncifcrf.gov

Received July 7, 2004; Revised August 18, 2004; Accepted August 24, 2004

The genome is burdened with repetitive sequences that are generally embedded in silenced chromatin. We have previously demonstrated that Lsh (lymphoid-specific helicase) is crucial for the control of heterochromatin at pericentromeric regions consisting of satellite repeats. In this study, we searched for additional genomic targets of Lsh by examining the effects of Lsh deletion on repeat regions and single copy gene sequences. We found that the absence of Lsh resulted in an increased association of acetylated histones with repeat sequences and transcriptional reactivation of their silenced state. In contrast, selected single copy genes displayed no change in histone acetylation levels, and their transcriptional rate was indistinguishable compared to Lsh-deficient cells and wild-type controls. Microarray analysis of total RNA derived from brain and liver tissues revealed that <0.4% of the 15 247 examined loci were abnormally expressed in Lsh–/–embryos and almost two-thirds of these deregulated sequences contained repeats, mainly retroviral LTR (long terminal repeat) elements. Chromatin immunoprecipitation analysis demonstrated a direct interaction of Lsh with repetitive sites in the genome. These data suggest that the repetitive sites are direct targets of Lsh action and that Lsh plays an important role as ‘epigenetic guardian’ of the genome to protect against deregulation of parasitic retroviral elements.


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