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Research

Our laboratory is focused on the transcriptional regulation of estrogen receptor (ER) signaling pathways by nuclear receptor co-factors. Our major interest is on a protein arginine (R) methyltransferase CARM1/PRMT4, a nuclear hormone receptor co-activator. Histone H3 methylation by CARM1 potentiates target gene activation by ER. Our ongoing studies include combining biochemical and functional genomic approaches to understand ER-regulated processes controlled by CARM1 and the mechanism by which histone arginine modification contributes to the epigenetic control of cancer cells. We will also employ mice genetics to decipher the significance of histone arginine methylation in tumor prevention, thereby facilitating the rational design of novel chemotherapy drugs by targeting the epigenome in breast cancer.

Research Focus:
  1. Can histone methylation and chromatin remodeling activity be uncoupled in the differential regulation of ER-target genes?
  2. Which kinases and pathways mediate the phosphorylation of CARM1?
  3. What are the downstream cellular events following CARM1-mediated arginine methylation?
  4. What is the functional role of CARM1 in estrogen-responsive cancers (e.g. breast and ovarian cancer)?
  5. What are the biological functions of ERa/b heterodimer in breast cancer? Are there natural compounds that promote ERa/b heterodimer formation?

Research Background:


ER belongs to ~50 hormone-regulated nuclear receptor (NR) transcription factor superfamily. Two ERs, ERa and ERb, regulate a number of gene products that are essential for the etiology and progression of breast cancer. The transcriptional potency of ERs is highly regulated by their cognate ligands, which trigger different conformations fostering association with co-activators or co-repressors via a similar LXXLL or L/IXXI/VI motif named NR box. To date, a large subset of the identified coactivators are involved in regulation of chromatin structure, either by covalently modifying histone tails or by remodeling the chromatin template. Recruitment of these coactivators to estrogen-responsive elements (EREs) increases the accessibility of the chromatin template for the basal transcriptional machinery, leading to the initiation of transcription. The p160 family of proteins are among the earliest identified NR coactivators, which directly associate with NR activation domain through their LXXLL motifs. The ER-associated p160 proteins serve as binding platforms for other coactivators such as p300/CBP and CARM1. These secondary coactivators act synergistically with p160 proteins to further remodel chromatin, resulting in the amplification of the output transcriptional signal.
 
CARM1, a coactivator associated arginine (R) methyltransferase, is involved in the activation of a number of transcription factors including NF-kB, p53, E2F1, and steroid receptors, among which transcriptional activation of estrogen receptors (ERs) by CARM1 is best characterized.

CARM1 methylates histone H3 at R2, 17, 26, and this methylation correlates with activation of ER-target gene. Loss of CARM1 leads to abrogation of the estrogen response and reduction in expression of some ER-target genes.  We recently identified a CARM1-associated complex, nucleosomal methylation activator complex (NuMAC), which includes multiple components of SWI/SNF chromatin remodeling complex.  SWI/SNF has also been implicated in ER-mediated transcriptional activation, and loss of SWI/SNF function is common in cancer progression.  Interestingly, we have recently found that CARM1 can be phosphorylated in vivo and that its phosphorylation inhibits its histone methyltransferase (HMT) activity.