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Pfeifer, Gerd, Ph.D.

Laboratory of Gerd Pfeifer, Ph.D.
The laboratory studies biological mechanisms involved in human cancer. Our goal is to determine the molecular mechanisms that are involved in formation of genetic changes (gene mutations) and epigenetic changes (DNA methylation and histone modifications) in the human genome.

The main research topic in the laboratory is epigenetic gene regulation in development and disease. Many genes are silenced by DNA methylation and by other repressive epigenetic mechanisms in human tumors. Methylated genes hold great promise not only as functionally relevant silenced genes involved in tumorigenesis but also as biomarkers for cancer diagnosis. We developed a sensitive method for analysis of DNA methylation on a genome-wide scale, the methylated-CpG island recovery assay (MIRA). MIRA is used to identify new commonly methylated genes in human tumors. Homeobox genes, known to be involved in developmental processes and tissue specification, are very frequently methylated in lung cancers and many other human tumors. We found that the mechanisms of cancer-specific DNA hypermethylation often involves targeting of specific DNA sequences, in particular homeobox genes, by the Polycomb repression complex and this pathway is already prevalent in inflamed tissue predisposing epithelial cells to malignant transformation. Using bioinformatics approaches, we are trying to uncover mechanisms dependent on DNA sequence features and DNA binding proteins that determine the specificity of DNA methylation changes in human cancers. We are also investigating changes in the epigenome in response to exposure of cells to environmental carcinogens including ultraviolet and ionizing radiation. Another project will attempt to establish a link between tissue aging and malignant transformation based on common changes in epigenetic regulation that underlie these processes. Very recently, previously unrecognized DNA bases, including 5-hydroxymethylcytosine, 5-formyl-, and 5-carboxy-cytosine, have been detected in certain mammalian tissues and cell types. We developed methodology to determine the sequence location of 5-hydroxymethylcytosine in mammalian DNA and found that it is targeted to promoters and gene bodies. In collaboration with Piroska Szabó’s lab, we showed that 5-methylcytosine is oxidized to 5-hydroxymethylcytosine selectively in the paternal genome of fertilized oocytes as part of a transgenerational epigenetic reprogramming mechanism. We showed that 5-hydroxymethylcytosine is strongly depleted in human cancers and could therefore be used as a biomarker for malignancy. Future work will focus on the distribution patterns and on the enzymology of 5-hydroxymethylcytosine formation and removal and its biological function in normal and malignant tissues.
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5-methylcytosine (5mC) can be oxidized enzymatically by the TET family of proteins to form 5-hydroxymethylcytosine (5hmC). This process occurs genome-wide in the sperm-derived paternal genome shortly after fertilization (Iqbal et al., 2011). One popular model proposes that 5hmC is a transient intermediate in DNA demethylation. However, this issue is still unresolved and needs to be investigated further. We found that 5hmC is strongly depleted in many types of human cancer and could be developed as a biomarker for malignant disease (Jin et al., 2011). One of our hypotheses is that defects in 5mC oxidation are responsible for altered DNA methylation patterns in tumors (and possibly other diseases). We have established and used methodology for precise quantification and genome-wide mapping of 5mC and 5hmC. Our goal is to determine the levels and the genomic distribution of 5hmC in normal human tissues and in malignant tumors. We will focus on several tumor types, including solid tumors and hematological malignancies, which are often characterized by mutations in one of the TET genes, TET2, a methylcytosine oxidase. We work on basic mechanistic studies of TET and TET-associated proteins (for example, CXXC domain containing proteins), their aberrations in cancer and on their functional roles in control of CpG island methylation and cell differentiation.
Iqbal, K., Jin, S.-G., Pfeifer, G.P., and Szabó, P.E. (2011) Reprogramming of the paternal genome upon fertilization involves genome-wide oxidation of 5-methylcytosine  Proc. Natl. Acad. Sci. USA 108, 3642-3647.
Jin, S.-G., Jiang, Y., Qiu, R., Rauch, T.A., Wang, Y., Schackert, G., Krex, D., Lu, Q., and Pfeifer, G.P. (2011) 5-hydroxymethylcytosine is strongly depleted in human cancers but its levels do not correlate with IDH1 mutations, Cancer Res. 71, 7360-7365.
Hahn, M.A., Qiu, R., Wu, X., Li, A.X., Wang, J., Zhang, H., Jui, J., Jin, S.G., Jiang, Y., Pfeifer, G.P.,* and Lu, Q.* (2013) Dynamics of 5-hydroxymethylcytosine and chromatin marks in mammalian neurogenesis, Cell Reports 3, 291-300.
Pfeifer, G.P., Kadam, S., and Jin, S.-G. (2013) 5-hydroxymethylcytosine and its potential roles in development and cancer, Epigenetics Chromatin 6(1):10.


Aging and the unstable epigenome

Various hypotheses have been put forward to explain the aging process at both the cellular and organismal level. We investigate if and how alterations of the epigenome contribute to the aging process. We analyze several epigenetic marks including DNA CpG methylation and chromatin modifications in cells and tissues that undergo aging in vitro and in vivo. This work includes an in-depth analysis of the epigenome at the level of histone modifications, DNA methylation and gene expression during the time course of human in vivo aging and in premature aging syndromes. The data will allow an estimation of the extent and specificity of epigenetic changes that occur during aging.

DNA methylation and cancer

5-methylcytosine (5mC) is a modified DNA base that plays an important role in gene regulation. One major focus of the laboratory is to study DNA methylation patterns in normal and cancer tissues (Rauch et al., 2008; Hahn et al., 2008; Rauch et al., 2009; Wu et al., 2010; Kalari, Jung et al., 2013). Despite of thousands of reports in the literature describing hypermethylation of specific genes in almost every type of human cancer, the mechanisms and biological significance of CpG island hypermethylation in tumors have remained obscure. Our work focuses on studies that will investigate the molecular pathways leading to DNA methylation changes in tumors. Our general hypothesis is that CpG island hypermethylation is driven by specific mechanisms, either by exogenous or endogenous carcinogenic agents, by inflammation, by oncogene activation leading to epigenetic changes, and/or by targeted mechanisms involving the Polycomb repression complex.
Rauch, T.A., Zhong,, X., Wu,, X., Wang,, M., Kernstine,, K.H., Wang,, Z., Riggs,, A.D., and Pfeifer, G.P. (2008) High-resolution mapping of DNA hypermethylation and hypomethylation in lung cancer, Proc. Natl. Acad. Sci. USA 105, 252-257.
Hahn, M.A., Hahn, T., Lee, D.-H., Esworthy, R.S., Kim, B.-W., Riggs, A.D., Chu, F.F., and Pfeifer, G.P. (2008) Methylation of Polycomb target genes in intestinal cancer is mediated by inflammation, Cancer Res. 68, 10280-10289.
Rauch, T.A., Wu, X., Zhong, X., Riggs, A.D., and Pfeifer, G.P. (2009) A human B cell methylome at 100 bp resolution, Proc. Natl. Acad. Sci. USA 106, 671-678.
Wu, X., Rauch, T.A., Zhong, X., Bennett, W.P., Latif, F., Krex, D., and Pfeifer, G.P. (2010) CpG island hypermethylation in human astrocytomas, Cancer Res. 70, 2718-2727.
Kalari, S., Jung, M., Kernstine, K.H., Takahashi, T., and Pfeifer, G.P. (2013) The DNA methylation landscape of small cell lung cancer suggests a differentiation defect of neuroendocrine cells, Oncogene 32, 3559-3568.

Mammalian neurogenesis

In collaboration with Dr. Qiang Lu, City of Hope, we are investigating changes in DNA cytosine modification and histone modifications in the developing mouse brain. The focus is on how these epigenetic events orchestrate gene expression patterns during neurogenesis (Hahn et al., 2013).
Hahn, M.A., Qiu, R., Wu, X., Li, A.X., Wang, J., Zhang, H., Jui, J., Jin, S.G., Jiang, Y., Pfeifer, G.P.,* and Lu, Q.* (2013) Dynamics of 5-hydroxymethylcytosine and chromatin marks in mammalian neurogenesis, Cell Reports 3, 291-300.

RASSF1 and the Hippo pathway

The biological significance of aberrant methylation in cancer (“driver” versus “passenger” methylation) is unclear (Kalari et al., 2010). Earlier, we identified and characterized the gene RASSF1A (Dammann et al., 2000). This gene undergoes methylation silencing in almost every type of human tumor (~1000 publications in PubMed). In the face of increasing numbers of cancer genome sequencing studies identifying mutations in critical genes, researchers are loosing sight of the breadth and significance of cancer-associated promoter hypermethylation. The RASSF1A pathway is a prime example highlighting the importance of epigenetic silencing events in tumors in the absence of frequent mutation of a gene. We identified RASSF1A as an upstream regulator of the Hippo tumor suppressor pathway (Guo et al., 2007). Interestingly, the one component of the Hippo pathway most frequently affected in human cancer is RASSF1A, which is silenced by promoter methylation in over 90% of human liver tumors, for example. Therefore, this promoter methylation is of high significance and we continue to study the biochemical function of RASSF1A and its related family members in the mammalian Hippo pathway and other tumor-relevant processes.
Dammann, R., Li, C., Yoon, J.-H., Chin, P.L., Bates, S., and Pfeifer, G.P. (2000) Epigenetic inactivation of a RAS association domain family protein from the lung tumour suppressor locus 3p21.3, Nature Genet. 25, 315-319.
Guo, C., Tommasi, S., Liu, L., Yee, J.-K., Dammann, R., and Pfeifer, G.P. (2007) The RASSF1A tumor suppressor protein is a component of a mammalian complex analogous to the Drosophila Hippo/Salvador/Lats tumor suppressor network, Curr. Biol. 17, 700-705.
Kalari, S., and Pfeifer, G.P. (2010) Identification of driver and passenger DNA methylation in cancer by epigenomic analysis, Adv. Genet. 70, 277-308.
Pfeifer, G.P., Dammann, R., and Tommasi, S. (2010) RASSF proteins, Curr. Biol. 20, R344-R345.


UV damage and repair

Exposure to ultraviolet (UV) causes melanoma and non-melanoma skin cancer in humans and UV-specific mutation patterns can be found in tumor genomes (Pfeifer and Hainaut, 2011). This work is an ongoing project supporting studies on UV-induced DNA damage, repair and mutagenesis. Part of the current work is aimed at investigating mechanisms of epigenetic changes induced by different types of UV radiation (Lahtz et al., 2013). One main goal is to obtain high-resolution DNA damage maps of UV-induced cyclobutane pyrimidine dimers (CPDs), the main DNA lesion induced by UVB radiation. We are currently developing methodology for base-resolution mapping of CPDs thus allowing a precise assessment of genomic UV damage and its relationship to features of DNA sequence and chromatin. Another goal is to study epigenetic changes in melanoma and relate them to genetic changes in the same tumors.
Pfeifer, G.P. and Hainaut, P., (2011) Next generation sequencing: emerging lessons on the origins of human cancer, Curr. Opin. Oncol. 23, 62–68.
Lahtz, C., Kim, S.I., Bates, S.E., Li, A.X., Wu, X., and Pfeifer, G.P. (2013) UVB irradiation does not directly induce detectable changes of DNA methylation in human keratinocytes, F1000Research, v1, online Feb 13, 2013. http://f1000r.es/np.


Lab Members

Thomas Dunwell
Postdoctoral Fellow
626-256-4673 ext. 62342
Maria Hahn
Staff Scientist
626-256-4673 ext. 65610
Seung-Gi Jin
Staff Scientist
626-256-4673 ext. 65926
Marc Jung
Postdoctoral Fellow
626-256-4673 ext. 63792
Sang-In Kim
Research Associate II
626-256-4673 ext. 62342
Wenying Xiong
Senior Research Associate
626-256-4673 ext. 64638
Xiaoying Zhang
Postdoctoral Fellow
626-256-4673 ext. 2342
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