Research Interests

Chromatin regulation of gene expression

DNA compaction into higher order
chromatin structures

Almost every cell in the body contains a copy of the genome in the form of DNA. The human genome contains about 3 million DNA bases that if stretched out would be about two meters long... per cell! Now multiply that by 37.2 trillion cells in the human body... and you have come upon one of the biggest challenges cells face. How does a cell, which ranges anywhere on the order of 8 and 30 microns in diameter, handle all of this genetic material?

Well it turns out cells utilize a unique organizational system for packaging genomic DNA. DNA is wrapped around proteins called histones which are then compacted into higher order structures - similar to coiling a hose or a ball of yarn. About 147 base pairs of DNA is wrapped around each histone which together is called a nucleosome.

Chromatin is not just a storage system. It turns out cells use chromatin to organize DNA into active and inactive regions. Genetic material such as genes and non-coding regulatory regions that need to be accessed regularly are usually in accessible euchromatin, or chromatin that is not compacted into higher order structures. Regions that are not active are kept in compact chromatin called heterochromatin. Organizing the genome in this way is ancient and chromatin compaction is a potential mechanism for regulating gene expression.

I am interested in understanding how chromatin structure regulates gene expression and how this structure is established early in development. 

The Non-coding Genome

When the human genome was sequenced in the early 2000's one of the most shocking discoveries was that only about 1.5% of the genome is considered protein-coding. So what's the other 98.5%? For a long time it was considered "junk DNA" -- garbage evolution left behind. This idea was very soon discarded as more and more functions of these non-coding regions were discovered.

Right place. Right time. Many of these regions are dedicated to regulating when and where genes will be expressed. Without this information, genes would be expressed haphazardly and specialized cell types like skin and brain cells couldn't exist. We would probably look more like e.coli (although even those little critters regulate their gene expression).

Enhancers are regulatory regions that contain binding sites for proteins called transcription factors which bind to DNA and interact with transcriptional machinery to turn genes on and off. Some enhancers control when genes are expressed during development. Others control which tissues or cells certain genes will be expressed in.

Image courtesy of LBNL
http://vis.lbl.gov/Vignettes/Drosophila/index.html

The best model for studying how enhancers govern gene expression is the humble fruit fly (Drosophila melanogaster). It turns out that enhancers in the early Drosophila embryo drive expression of developmental genes in beautiful patterns. These patterns are not purely for aesthetic - they give each cell (or nucleus) in the embryo a unique identity, dictating which structure that cell will eventually become. Miraculously, development gets these patterns right almost every time, even with dramatic changes in environment.

So how do enhancers create transcriptional precision during embryonic development? This question is the over-arching theme of my current thesis research.

Non-coding RNA. Enhancers aren't the only members of the non-coding community. Members under the non-coding umbrella are repeats, gene introns, heterochromatin, transposons and non-coding RNA. Non-coding RNA is exactly what it seems - RNA that is not translated into proteins (often). Non-coding RNA comes in many varieties - usually classified by size. MicroRNAs are less than 30 base pairs long and regulate gene expression by degrading mRNAs in a sequence specific way.  Long non-coding RNA are over 200 nucleotides and have been shown to be important for X chromosome inactivation and as scaffolds for RNA binding proteins.

How do non-coding RNAs, like long non-coding RNAs or miRNAs, regulate transcriptional patterns during early embryonic development? 

Scientific Philosophy: Translational Basics

Having worked both in industry and academia, I have found that the research I love doing best is what I call "translational basics" - basic science that has real human impact.

Traditionally, translational research is disease focused with development of treatments taking priority over understanding disease biology. However during my brief time working in a cancer genomics lab, I realized that the low hanging fruits of cancer treatment have been mostly picked clean and that the next big advance in eradicating something as complex and widespread as cancer will come from basic science answering fundamental questions about how cells normally function and how these functions are altered in disease states.

These answers will not necessarily come from studying human cells. Some of the most profound discoveries in human history were made in model organisms such as flies, worms, yeast, and bacteria. Continued support for basic research is imperative for confronting some of the greatest challenges in human history.

As a scientist I have to follow my intellectual curiosity in basic scientific research. But what gets me out of bed in the morning is the hope that this work will mean something either for the person sitting next to me on the bus today or a future scientist ten years down the road (hopefully I will have graduated by then...).