Kathrin Muegge, M.D.
Dr Muegge studies molecular mechanisms that alter chromatin structure and function during murine development. She discovered several links between chromatin modifiers, including nucleosomal remodeling and DNA methylation.
The work focuses on chromatin changes during normal cellular differentiation and during the reverse process of nuclear reprogramming. Her studies provide insights how stable gene expression is achieved, how cells maintain a proper phenotype, and how this process may be disturbed in pathologic conditions including cancer.
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 lymphoid-specific helicase (Lsh).
Lsh is a chromatin remodeling protein that we 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 into a number of basic biologic processes that involve epigenetic modifications such as transcription, imprinting, mitosis and cellular transformation.
Selected Key Publications
Lsh, chromatin remodeling family member, modulates genome-wide cytosine methylation patterns at nonrepeat sequences.Proc Natl Acad Sci U S A. 108: 5626-31, 2011. [ Journal Article ]
Treatment of breast cancer cells with DNA demethylating agents leads to a release of Pol II stalling at genes with DNA-hypermethylated regions upstream of TSS.Nucleic Acids Res. 39: 9508-20, 2011. [ Journal Article ]
- EMBO J. 31: 972-85, 2012. [ Journal Article ]
CG hypomethylation in Lsh-/- mouse embryonic fibroblasts is associated with de novo H3K4me1 formation and altered cellular plasticity.Proc Natl Acad Sci U S A. 111: 5890-5, 2014. [ Journal Article ]
Genome-wide DNA methylation patterns in LSH mutant reveals de-repression of repeat elements and redundant epigenetic silencing pathways.Genome Res. 24: 1613-23, 2014. [ Journal Article ]
Dr. Muegge obtained her M.D. degree at the Medical School Hannover, Germany. During her postdoctoral period she worked on cytokines and T cell development in the Laboratory of Molecular Immunoregulation of Dr. Joost Oppenheim and Dr. Scott Durum. As a Principal Investigator at the National Cancer Institute in Frederick, she now investigates in the Laboratory of Cancer Prevention chromatin organization during embryonic development and in tumor progression.
|Yafeng He Ph.D.||Postdoctoral Fellow (Visiting)|
|Kai Ni Ph.D.||Postdoctoral Fellow (Visiting)|
|Andrew Schwader||Postbaccalaureate Fellow|
|Xiaoping Xu Ph.D.||Postdoctoral Fellow (Visiting)|