Computational Biology Program
New York University
April 30, 2013
The effect of enhancers on the transcriptome and chromosomal interactome in developing lymphocytes
The development of lymphocytes is driven by V(D)J recombination, which creates a wide variety of receptors that target foreign pathogen. This process rearranges multiple gene segments at the antigen receptor loci and is tightly regulated to ensure that rearrangement only occurs within the appropriate locus, stage of development and cell lineage. Enhancers of the antigen receptor loci are thought to play an important role in the control of V(D)J recombination. They act through intra-locus interactions that are linked to changes in transcription and locus accessibility. However, the role of long-range interactions between chromosomes in gene regulation has not been studied in any depth. This is changing as a result of improvements in sequencing technology combined with the development of chromosome conformation capture (3C) based techniques. These advances mean we can now examine long-range interactions on a global scale. Although the use of genome wide 3C-based techniques such as 4C-Seq, Hi-C and 5C are rapidly increasing, the methodology for analyzing these complex data sets is lagging behind and there are currently no ideal approaches for extracting functional information from the data. We are therefore developing robust computational methods to analyze 4C-Seq data and identify genomic regions that contact enhancers involved in regulating V(D)J recombination and lymphocyte development. Additionally, co-expressed genes are thought to colocalize in three-dimensional space within the nucleus. To investigate this on a genome-wide scale we will integrate 4C-Seq data with RNA-Seq data to determine the functional relationship between spatial organization and transcription in this model system.