The encyclopedia of DNA - Part III

The ENCODE project effectively marked the transition from genomics to functional genomics. The goal of the Human Genome Project was to type the entire human genome. Once that was achieved people realized they had just scraped the tip of the iceberg. Today, the goal of functional genomics is go one step beyond DNA sequences, and understand the dynamics of gene expression, transcription, translation and all the complex pathways that lead from DNA to the making of proteins.

In order to do this, the main goal of functional genomics is to annotate regulatory elements of the genome, in other words, elements that regulate gene expression and transcription. For example, proteins called transcription factors bind to regulatory sequences and favor transcription of a gene into mRNA. Last time we learned about regulatory sequences such as promoters and enhancers, and how the ENCODE project has found a vast amount of these sequences, in particular outside and far away from the genes they regulate.

Previously, we also learned about chromatin, the "yarn" of DNA inside the nucleus, and how its configurations affect gene expression. We also learned about transcription factories inside the chromatin, where genes are recruited and transcribed.

In order to transcribe a gene, the two helices of DNA where the gene sits need to be separated. This will allow the RNA polymerase to access the strand where the gene sits and transcribe it. In other words, in order to be expressed, a gene needs to be accessible. To explore how "accessible" a gene is in a specific chromatin configuration, people have employed the technique of mapping regions called hypersensitive sites. These sites are highly accessible to certain enzymes called nucleases, and promoters and most regulatory elements are found in chromatin sites that are hypersensitive to one endonuclease in particular, called DNase I. Therefore, mapping DNase I hypersensitive sites (DHSs) is an efficient way of identifying regulatory DNA regions.

In [1], Thurman et al. identified nearly 2.9 million genome-wide DHSs across 125 cell types.

"Annotating these elements using ENCODE data reveals novel relationships between chromatin accessibility, transcription, DNA methylation and regulatory factor occupancy patterns. [. . .] Patterning of chromatin accessibility at many regulatory regions is organized with dozens to hundreds of co-activated elements, and the transcellular DNase I sensitivity pattern at a given region can predict cell-type-specific functional behaviours."

Chromatin accessibility is what allows transcription factors to bind to the DNA region to be transcribed. Hence, which sites are accessible and which are not plays an important role in gene expression. When transcription factors bind to their target sites, they initiate chromatin remodeling and the recruitment of other chromatin elements. These local perturbations make certain stretches of DNA accessible to nucleases, DNase I in particular.

[1] Robert E. Thurman, Eric Rynes, Richard Humbert, Jeff Vierstra, Matthew T. Maurano, Eric Haugen, Nathan C. Sheffield, & Andrew B. Stergachis, et al. (2012). The accessible chromatin landscape of the human genome Nature DOI: 10.1038/nature11232