Mechanisms of condensin-mediated gene regulation in C. elegans

Research summary Regulation of transcription is essential for cell function. In eukaryotes, diverse mechanisms control transcription through chromatin structure and organization of DNA within the nucleus. Histone modifications modulate the activity of gene regulatory elements and regulate binding of proteins that form transcriptionally active and inactive compartments. Structural maintenance of chromosomes (SMC) complexes bind and translocate on DNA, forming loops that bring distant sites into contact. As the molecular activities of individual chromatin modifiers and SMC complexes are being studied, it is important to determine how they integrate with each other to control transcription during development and differentiation. Our research program addresses the functional interactions between SMC complexes, chromatin, and transcription around three topics. The first focuses on condensin, a eukaryotic SMC complex that has been challenging to study in vivo because it is essential for cell division and binds chromosomes transiently during mitosis. In the nematode Caenorhabditis elegans, a hermaphrodite-specific condensin functions throughout the cell cycle to repress X chromosome transcription for dosage compensation. Condensin DC also controls histone modifications, providing an excellent system to study integration of SMC activity and chromatin modifiers for transcription regulation. The second topic focuses on the interaction between condensin and cohesin, another SMC that regulates the organization of eukaryotic genomes during interphase. As cells progress from interphase to mitosis, cohesin binding and activity decreases while condensin’s increase and transcription is silenced. This transition is key to regulation of cell-type specific transcriptional programs during differentiation. By addressing how condensin DC interacts with cohesin on the X chromosomes, we believe our work can provide insights into the interphase to mitotic transition of the eukaryotic genomes. The third topic is regulation of RNA Polymerase III, which transcribes a diverse array of small functional RNAs, including tRNAs. RNA Pol III regulation is relatively understudied and is important for protein translation in health and disease. Due to unique chromosomal distribution of tRNA genes, our work in C. elegans dosage compensation puts us in an ideal place to study the mechanisms that regulate RNA Pol III transcription. In the next five years our research will provide significant insights into how cohesin, condensin and chromatin work together to regulate transcription during development and differentiation. Our program is also evolving to address environmental gene regulation and RNA Pol III transcription – new and important areas of study to understand basic mechanisms of genome organization and function throughout the life of an organism.