Lsh, a guardian of heterochromatin Epigenetic modifications comprising DNA methylation and histone modifications are crucial for organization of the genome into active chromatin (euchromatin) and repressed chromatin (heterochromatin). The functional organization of chromatin is important for regulation of transcription, cellular differentiation, imprinting and normal mitosis. Our group studies the role of epigenetic modifications that control chromatin structure in particular DNA methylation during normal embryonic development and during cancer development. The current focus of our studies is to understand the molecular mechanisms and biological role of Lsh. Lsh (lymphoid specific helicase) is a chromatin remodeling protein that our group has previously identified, cloned and characterized. Lsh is predominantly found in lymphoid tissues in the adult animal, but it is ubiquitously expressed during embryogenesis. Lsh is a crucial factor for normal embryonic development since targeted deletion of Lsh leads to death of the newborn animal. Lsh is a component of pericentromeric heterochromatin and Lsh deficiency results in a greatly perturbed heterochromatin organization with loss of DNA methylation and altered histone tail acetylation and methylation. As a functional consequence of perturbed pericentromeric heterochromatin we observe aberrant reactivation of 'parasitic' elements (such as endogenous retroviral elements) and abnormal mitosis with amplified centrosomes and genomic instability. Thus Lsh is a major epigenetic regulator that controls DNA methylation patterns and is crucial for normal heterochromatin structure and function. We are currently testing the role of Lsh and genomic demethylation in tumor progression. These studies should provide insights in a number of basic biologic processes that involve epigenetic modifications such as transcription, imprinting, mitosis and cellular transformation.

National Institute of Health (NIH)
Division of Basic Sciences - NCI (NCI)
Intramural Research (Z01)
Project #
Application #
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Basic Sciences
United States
Zip Code
Xi, Sichuan; Geiman, Theresa M; Briones, Victorino et al. (2009) Lsh participates in DNA methylation and silencing of stem cell genes. Stem Cells 27:2691-702
Zhu, Heming; Geiman, Theresa M; Xi, Sichuan et al. (2006) Lsh is involved in de novo methylation of DNA. EMBO J 25:335-45
Fan, Tao; Hagan, John P; Kozlov, Serguei V et al. (2005) Lsh controls silencing of the imprinted Cdkn1c gene. Development 132:635-44
Huang, Jiaqiang; Fan, Tao; Yan, Qingsheng et al. (2004) Lsh, an epigenetic guardian of repetitive elements. Nucleic Acids Res 32:5019-28
Fan, Tao; Yan, Qingsheng; Huang, Jiaqiang et al. (2003) Lsh-deficient murine embryonal fibroblasts show reduced proliferation with signs of abnormal mitosis. Cancer Res 63:4677-83
Yan, Qingsheng; Huang, Jiaqiang; Fan, Tao et al. (2003) Lsh, a modulator of CpG methylation, is crucial for normal histone methylation. EMBO J 22:5154-62
Muegge, Kathrin (2003) Modifications of histone cores and tails in V(D)J recombination. Genome Biol 4:211
Muegge, Kathrin; Young, Howard; Ruscetti, Francis et al. (2003) Epigenetic control during lymphoid development and immune responses: aberrant regulation, viruses, and cancer. Ann N Y Acad Sci 983:55-70
Geiman, T M; Muegge, K (2000) Lsh, an SNF2/helicase family member, is required for proliferation of mature T lymphocytes. Proc Natl Acad Sci U S A 97:4772-7
Lee, C K; Kim, K; Geiman, T M et al. (1999) Cloning thymic precursor cells: demonstration that individual pro-T1 cells have dual T-NK potential and individual pro-T2 cells have dual alphabeta-gammadelta T cell potential. Cell Immunol 191:139-44

Showing the most recent 10 out of 11 publications