Characterizing in Vivo Chromatin Folding Landscape of IgH locus on Chromosome 12

Type of Award: Catalyst
Date Awarded: September 2013
Award End Date: August 2015
Amount Awarded: $ 199,998.00
PI(s): Jie Liang, PhD, UIC; Amy Kenter, PhD, UIC; John Marko, PhD, NU;

Abstract: Gene expression is controlled by combinations of regulatory elements that interact over long distances. Chromosome conformation capture (3C) and related techniques have led to the discovery of looping interactions among distant chromosomal elements, thereby providing a mechanism for long range enhancer function. However, the looping events responsible for immunoglobulin (Ig) gene rearrangements, which are key events in the assembly of functional Ig genes required for mature humoral immune responses, are currently unknown. Aberrant V(D)J joining occurs at surprisingly high frequency and often leads to recurrent chromosomal translocations with specific oncogenes. The chromosomal translocations originating from aberrant V(D)J joining are precipitating factors in leukemiagenesis. Recurrent nonrandom chromosomal translocations may be due to spatial proximity of broken chromosomal ends at the time of V(D)J joining. We present here two highly inter-related projects that requires the expertise of each investigator to create exciting new synergies with the potential for cutting edge new technologies and experimental insights. Using new methodology under development by Dr. Kenter, a defined segment of chromatin will be isolated in vivo and its biophysical properties will be measured by Dr. Marko using his single-chromatin fiber nano-tweezers technology. Dr. Kenter has generated massively parallel large scale measurements of long range chromosomal interactions spanning the Igh locus and the surrounding areas. Using this information, Dr. Liang will apply his novel sequential Monte Carlo algorithms, built upon a polymer chromosome model of explicitly constructed chromatin chains , to assemble ensemble 3D chromatin structures of the Igh locus. This information will be leveraged to better understand sites within the Igh locus that are at high risk for chromosomal translocations and the propensity toward leukemia and lymphoma, and will lay the groundwork for efficient large scale modeling of full chromosomes.