Laboratory Jumana AlHaj Abed
Chromatin structure and gene regulation
AlHaj Abed lab focuses on understanding how maternal and paternal chromosomes communicate using genomic approaches and super-resolution imaging. Our lab explores the fundamental mechanisms governing the three-dimensional folding of homologous chromosomes within the nucleus and how that contributes to gene regulation in Drosophila and mammals.
Recently, imaging and biochemical approaches demonstrated that gene regulatory programs are associated with a non-random genome organization, from the nucleosome level up to whole chromosome territories, including domains, loops, and repressed or active chromatin compartments.
Out of all cis and trans genomic interactions in the nucleus, the unique contribution of each parental chromosome sequence and folding to genome organization and function is poorly understood. This has been mainly due to the scarcity of tools that can distinguish parental chromosome contributions because of their high level of sequence similarity. Interestingly, homologous chromosome interactions are essential for genome function in Drosophila and mammals. In Drosophila, homologs are paired end-to-end during interphase in somatic cells, and transvection, or pairing-dependent gene regulation, is reported at many loci. This contrasts with the transient occurrence of homolog pairing in mammals, which is associated with critical processes, such as DNA repair, cell fate establishment and mono-allelic expression.
More recently, an increasing number of mammalian loci have been shown to support somatic homolog pairing. In Drosophila, our allele specific studies in embryos showed that trans homolog interactions are structured and multilayered, consisting of trans homolog loops and domains. In fact, in established cell lines we showed that there are different types of trans homolog domains that vary in their pairing registration. More in-register paired domains associate with both high and low levels of gene expression, whereas less in-register paired domains associate exclusively with low levels of gene expression. These novel findings provide a first-time view of how the sequence registration of paired homologous chromosomes could contribute to gene expression.
The goal in AlHaj Abed laboratory is to understand allele-specific principles of genome organization within active or repressed biological contexts in different species. Our focus is on understanding: i) how parental chromosomes (homologs) are folded at different genomic scales and contribute to trans homolog gene regulation in different tissue-specific contexts, ii) which factors and/or steps lead to pairing and unpairing events, and iii) how homolog folding is affected in disease states.
Some of the questions we are interested in addressing are: What are the factors that facilitate homolog pairing interactions and are structural maintenance of chromosomes proteins (SMCs) involved? How does pairing registration contribute to differences in homologous pairing folding and gene function? How do the differences in paired homolog folding relate to epigenetic states?
To answer these questions, we tackle the challenge of sequence similarity of parental chromosomes by using novel allele-specific approaches at the genomic and single-cell level. This includes: i) imaging DNA and RNA at super-resolution using sequential OligoSTORM, ii) performing allele-specific Hi-C and RNA-seq, and iii) developing live imaging tools to understand trans homolog transcriptional dynamics. In addition, we apply those tools to mammalian systems to gain insights into common molecular mechanisms governing parental chromosome organization in diverse species.