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Laboratory of Cancer Epigenetics and Signaling

Fei Chen, PhD

Principal Investigator

Pathology and Physiology Research Branch

National Institute for Occupational Safety and Health

Professor (Adjunct)

Dept of Basic Pharmaceutical Sciences

West Virginia University

 

1095 Willowdale Road

Morgantown, WV 26505

Tel: (304) 285-6021

Fax: (304) 285-5938

Email: LFD3@cdc.gov

 

Research: NF-kB, intracellular signaling and histone methylation in carcinogenesis
 
            The broad focus of Chen's lab is to investigate genetic and epigenetic regulations of genes in human lung cancer related to environmental or occupational exposure to mineral dust and carcinogenic metals.  More specifically, the lab employs biochemical approaches to elucidate molecular mechanisms by which the expression and function of genes contributing to lung inflammation and tumorigenesis are altered.  One of the key signaling events in carcinogenic gene regulation is the activation of kinases and transcription factors, such as JNK and NF-kB.  A principal question to be addressed is how extracellular inducers, such as ROS, cytokines and carcinogenic metals, perturb the intracellular regulatory circuits that control cross-talk, durability and potency of JNK and NF-kB signalings.  NF-kB had been previously demonstrated as an oncogenic transcription factor for the expression of anti-apoptotic proteins, oncogenes and growth factors.  However, recent studies by Chen's lab suggested that genetic disruption of NF-kB causes sustained ROS generation, JNK activation and the acquisition of the transformative phenotype of the cells in response to arsenic or other environmental stress agents. 
 
            Accumulating evidence suggests that in addition to their impacts on genetic regulation, many carcinogenic agents cause malignant transformation of the cell through altering the epigenetic landscapes of histone proteins and the genomic DNA.  The status of histone methylation, esp. on the N-terminal tails of histones H3 and H4, directly determines the accessibility of the regulatory factors on the genes packed in the condensed chromatin fibers.  The lysine residues of histones can be modified by mono-, di- or tri-methylation.  It has been generally viewed that tri-methylation of lysines 4 and 36 of histone H3 (H3K4me3 and H3K36me3) causes de-condensation of the chromatin to form euchromatin for active gene transcription.  In contrast, tri-methylation of lysines 9 and 27 of histone H3 (H3K9me3 and H3K27me3) is refractory for gene expression due to the formation of the highly condensed heterochromatin architecture.  Chen's lab had previously identified a mineral dust-induced gene, mdig.  The latest data revealed an involvement of mdig protein in demethylation of H3K9me3.  The mdig protein contains a JmjC domain, a signature motif for di- or tri-methyl demethylases.  An ongoing project is to test the hypothesis that mdig promotes proliferation and trumorigenic transformation of the lung cells through antagonizing H3K9me3 and the consequent de-repression of the checkpoint mechanisms for cell cycle and gene expression.
 
Recent graduate student and postdoc projects:
 
1.  Arsenic regulation on miRNAs;
2.  Alternative splicing and IRES-dependent translation of Gadd45a in response to arsenic;
3.  Mdig antagonizes H3K9me3 in lung cancer;
4.  JNK1-Egr1-EZH2 cascade in HCC;
5.  NEMO/IKKg in Jmjd3-induced demethylation of H3K27me3 and expression of Perp.
 
 Lab members:
 
 From left to right: Deepak Bhatia (graduate student); Terry Meighan (research Biologist); Kevin Beezhold (graduate student); Kharlya Carpio (intern); Yadong Zhang (postdoc); Fei Chen (PI)
 
 
NF-kB, JNK, EZH2, and H3K27me3
 
Using NEMO/IKKg deficiency (IKKg-/-) MEFs, we noted that disruption of NF-kB signaling compromised induction of Jmjd3, a demethylase for H3K27me3, by arsenic.  Intriguingly, the level of a H3K27 specific methytransferase, EZH2, was elevated in these arsenic-treated IKKg-/- cells in which JNK activation was enhanced.  Decrease in Jmjd3 as well as increase in EZH2 causes an appreciable enhancement of H3K27me3 in these IKKg-/- cells.  In wt MEFs, in contrast, arsenic induces expression of Jmjd3 and represses EZH2, leading to a remarkable dose-dependent reduction of H3K27me3.  Based on these data, we hypothesize that NF-kB and JNK have opposite effect on H3K27me3.  NF-kB-Jmjd3 signaling may be responsible for the demethylation of H3K27me3, wherease JNK-EZH2 pathway fosters formation of H3K27me3.  
 
 
                                http://www.hsc.wvu.edu/som/pathology/cellularPathology.asp
 
Subpages (1): Publications
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Jun 16, 2008, 10:35 AM
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Jun 16, 2008, 9:27 AM
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