GenReg: Laboratory of Genome Regulation

Research Interests:

Gene Regulation and Epigenetics
Molecular Mechanisms in Cancer
Identification of Therapeutic Targets in Cancer

Approaches:

 Cell culture  and xenograft rodent models of cancer
 Biochemical and molecular biological approaches
 Genome-wide approaches

melanoma

 

Research Focus: Gene Regulation and Cancer

The human genome contains more than twenty thousand genes. Cells need to tightly control when, where, and how much these genes are expressed during the development and functioning of organisms. Various environmental influences can disrupt the normal gene expression programs through genetic and epigenetic changes. Such disruptions are known to play central roles in disease processes like cancer. Therefore, research into the mechanisms of the factors involved in gene regulation is critical for a better understanding of cancer, and ultimately, for the design of cancer therapies targeting these factors and the pathways they control.

Chromatin Regulation in Normal and Cancer Cells

One of the ways cells control gene expression involves regulation of chromatin, the packaging of DNA in the cell nucleus. The mechanisms for this type of epigenetic control include the addition and removal of chemical groups to the histone proteins that package the DNA.

In earlier studies, we have studied the mechanisms of enzymes that catalyze chemical modifications of histones and their effects on gene expression using the budding yeast as a model organism (reviewed in Emre and Berger, 2006). For instance, we have identified aspects of how different histone modifications affect each other for the activation of gene expression (Lo et al, 2001). In particular, we have identified the activity and mechanisms of enzymes called ubiquitin proteases (UBP) that remove ubiquitin moieties from histones in gene activation (Henry et al, 2003; Ingvarsdottir et al, 2005), and silencing of chromosomal regions (Emre et al, 2005; reviewed in Emre and Berger, 2004). More recently, in another line of work, we have identified JAK2 kinase dependent histone H3 phosphorylation and JMJD2C dependent histone H3 demethylation, two distinct but cooperating histone modification pathways as critically important for human B cell cancer (lymphoma) subtypes (Rui et al, 2010), suggesting that these processes may be targeted simultaneously for a synergistic effect as lymphoma therapy in the future.

Transcription Factors in B-cell Cancers

Another class of molecules central to the control of gene expression is transcription factors. These proteins help activate or suppress gene activity mostly through binding to specific sequences on the DNA, in or near genes, and recruit chromatin modification and gene transcription enzymes. Aberrant transcription factor structure or expression are implicated in disease processes, including cancer.

Earlier, we have studied the determinants important for the interaction between two tumor suppressor transcription factors, p53 and ING1. During recent work, we have uncovered the mechanisms and the genome-wide targets of some of the key cancer-promoting transcription factors, such as SPIB and IRF4 important in aggressive mature B-cell cancers, namely diffuse large B-cell lymphoma and multiple myeloma (Shaffer et al, 2008; Lenz et al, 2008; Yang et al, 2012).  Essential nature of these transcription factors in B-cell cancers, combined with their modes of action that we have identified is expected to help in the design of future therapies for these cancers.

Transcriptional Regulation in Skin Cancer

Advanced stage melanoma skin cancers are generally resistant to current therapies, and are therefore deadly. Previous studies implicate certain parallels in transcriptional regulation in B-cell cancers and melanoma.  Using a combination of cellular, biochemical and genome-wide approaches we are currently studying the role of this regulation in melanoma skin cancers.

 

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