Decoding the mammalian regulatory genome

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Despite completion of the human genome sequence 16 years ago we are currently not able to determine the function of the vast majority of this sequence. We understand how to read the sequence code within gene coding regions but these are 98% of the genome are gene regulatory elements that turn genes on/off in specific cells. These regulatory elements are the instructions for specific cell types. They cause the activation of different groups of genes in brain, blood and heart cells, for example. My research studies an activating type of regulatory element called enhancers. Enhancers are short sequences of about 500 bases that turn on specific genes when their protein product is needed. Although we know that enhancers are important for the proper development of complex organisms and are often the cause of specific differences in the body plan of different species we actually know remarkably little about the sequence code that gives them their function. We are not able to scan the genome sequence to find enhancers or interpret the function of different parts of the sequence when we do know the location of an enhancer. This is like having a book written in a language you can't read. Or, as we have fully sequenced genomes for more than 100 mammals, an entire library of books that you can't read. Recent work by my team has determined new information about the enhancer regulatory code. We used computational biology to predict the conserved functional units in pluripotent stem cell (PSC) enhancers using sequence conservation across 5 mammals. We found there is a larger number of sequence units contributing to enhancer activity than was previously appreciated. More than 10 sites that bind transcription factors are required for robust enhancer activity. We now understand enough of the code for PSCs to make synthetic sequences with function similar to natural enhancers; we can write our own sentences. Over the next 5 years my research team will expand the approach we developed in one cell type to predict the enhancer regulatory code for multiple different cell types. We will address three key questions: 1) Why are so many transcription factor binding sites needed for enhancer activity? 2) How is the regulatory code different in different cell types? 3) What is the best computational approach to fully decode mammalian genomes? In the long term fully decoding genome sequences will allow us to predict how regulatory sequence changes will affect the expression of specific genes. This will have widespread impact on our understanding of development, evolution and the underlying cause of phenotype variation in populations.