lay readers' summary

In humans and other eukaryotes, the long linear DNA molecules called chromosomes are tightly condensed inside a small nucleus. In each human cell, ~2 m of DNA is packaged into a ~0.01 mm nucleus. DNA packaging regulates the access of important cellular machinery to DNA. For instance, packaging is loosened for gene expression, which requires the transcriptional machinery to use DNA as a template to synthesize messenger RNA. In the Ercan lab, we study how DNA packaging regulates transcription.

The challenge of packaging DNA without tangling is met by proteins that bind to and form a protein-DNA structure called chromatin. Chromatin proteins are evolutionarily conserved from single-cell eukaryotes to humans. Therefore many researchers, including our laboratory use experimentally tractable organisms to study chromatin. We use C. elegans, a small invertebrate, and S. cerevisiae, the bakers yeast, to study a particular group of chromatin proteins called condensins, which regulate chromosome condensation during cell division and transcription during interphase.

An excellent system to study condensin and transcription is the X chromosome dosage compensation in C. elegans. Dosage compensation is the process by which X chromosome transcription is equalized between females (XX) and males (XY). Dosage compensation is necessary because having an extra chromosome or missing a chromosome is lethal or causes developmental problems in animals (e.g. trisomy of chromosome 21, aka Down syndrome). In C. elegans, a specialized condensin complex binds to and regulates chromatin to reduce transcription from both X chromosomes by half in XX hermaphrodites, thereby equalizing X chromosomal transcript level to that of XO males (in C. elegans there is no Y chromosome).

Research in our lab and others revealed a two-step targeting strategy for condensin binding to chromosomes: recruitment and spreading. Recruitment is accomplished in part by short DNA sequence elements that are recognized by recruiter proteins. Spreading mechanism remains elusive, but occurs linearly from recruitment site to gene regulatory regions such as promoters and enhancers. Condensin binding results in specific changes in chromatin modifications and in the three-dimensional structure of the chromosomes. Our current research aims are to determine the molecular mechanisms of condensin recruitment, spreading, and transcription repression. This is important because condensin mutations are associated with certain developmental diseases and cancers. Accordingly, we are currently funded by the National Institute of General Medical Sciences.