Abstract
My research aims to understand the role of three-dimensional (3D) chromatin structure in gene
regulation. This involves studying associations among genotype, histone modifications,
transcription factor binding, non-coding RNAs, chromatin interactions and gene expression. In
order to transform this genome-wide information into new biological discoveries, my laboratory
develops scalable and interpretable computational methods based on statistics, graph theory and
machine learning. Our recent focus is to address an important gap in the current knowledge of
the role of 3D chromatin structure in gene regulation. That is, we aim to define how genotypic
variation affects 3D organization of gene promoters, and in turn, their expression. To achieve this
at a genome-wide scale is an ambitious goal, because it requires having at a minimum, genotype,
gene expression and chromatin interaction profiles in pure populations of specific cell types from
a large number of donors. However, my laboratory is uniquely positioned to perform this research
because: i) we are involved in a study at the La Jolla Institute (LJI-R24AI108564) that has already
genotyped ~100 donors and expression-profiled more than 15 different pure populations of
human immune cell types, and we have access to the same samples for chromatin interaction
mapping, ii) in collaboration with other groups at LJI, we have already discovered a prototypical
example of an interaction quantitative trait locus (iQTL) that alters and rewires interactions from
the promoter of a specific gene that is associated with asthma susceptibility, iii) we have the
necessary expertise and proven track record in experimental design and computational analyses
of various chromatin conformation capture assays. Leveraging the resources available at LJI and
our expertise in the field, we will build a unique research program around the novel concept of
iQTLs. The emerging set of three main questions we propose to address within the next five years
are: Q1) How do we define cell-type-specific iQTLs for common genetic variants? Q2) What is
the extent of overlap between iQTLs and GWAS SNPs? Q3) Can we build predictive models for
the cell-type specificity of chromatin interactions and iQTLs? Although we propose to define iQTLs
only in two abundant, easily accessible, and highly disease-relevant immune cell types, the
concept of iQTLs is equally important in other cell types implicated in diseases with a genetic
component. Hence, the proof-of-concept developed by this work, without a doubt, will open up a
new field in studying a previously uncharacterized role for disease-susceptibility variants,
specifically non-coding SNPs, from genome-wide association studies (GWAS) in gene regulation.