Eukaryotic genomes must be condensed to fit inside a small nucleus yet still allow access for gene expression. DNA is packaged hierarchically starting from nucleosomes to chromatin fibers that fold and organize into individual chromosome territories within the nucleus. Packaging at each level regulates transcription. For instance, nucleosomes reduce DNA accessibility to transcription factors and RNA Polymerase. Looping of chromatin fibers mediate regulatory interactions between enhancers and promoters. The link between higher level of chromosome organization and gene expression remains unclear. At the domain-scale, genes across hundreds of kilobases of DNA can be coordinately regulated in clusters – for example the Hox gene cluster and the X chromosome. The goal of our lab is to uncover the molecular mechanisms that specify and regulate large chromosomal domains. The questions that drive our current research are: How are chromosomal domains specified and targeted for gene regulation? What are the transcriptional mechanisms that regulate multiple genes across a domain? What are the functional and evolutionary consequences of domain-scale gene regulation?
To understand the mechanisms of domain-scale gene regulation, we mainly study X chromosome dosage compensation in Caenorhabditis elegans. Dosage compensation is an essential developmental process that equalizes X chromosome transcription between sexes in many animals, including humans. Although strategies differ between species, in the model organisms M. musculus (mouse), D. melanogaster (fly) and C. elegans (worm), multi-subunit dosage compensation complexes (DCC) bind to and regulate X chromosome transcription specifically in one sex. The DCC subunit compositions indicate that the different dosage compensation systems co-opted and targeted distinct sets of gene regulatory mechanisms to the X chromosome. Thus, the diverse strategies of X chromosome dosage compensation provide a unique and experimentally tractable window into the mechanisms that target and regulate transcription across large chromosomal domains.
In C. elegans, the DCC specifically binds to and reduces transcription from both X chromosomes by half in XX hermaphrodites. The core of the DCC is a condensin complex, which belongs to the evolutionarily conserved structural maintenance of chromosomes (SMC) family of complexes. Condensins are essential for chromosome condensation and segregation during cell division, and regulate genome organization and gene expression during interphase. Defects in SMC complexes, including condensins disrupt normal chromosomal functions in a wide range of developmental diseases and cancer. Our research on the C. elegans DCC and S. cerevisiae condensin contributes to the mechanistic understanding of SMC complexes in normal development and in disease.
To read more about our current projects visit: https://sites.google.com/site/ercanlab/research. For a lay reader’s summary visit: https://sites.google.com/site/ercanlab/home/lay-readers-summary.