Academic Background:
Kirsten Hagstrom received her B.A. in Biology and Music from Oberlin College in 1989, and her Ph.D. in Molecular Biology from Princeton University in 1998. She was subsequently a postdoctoral fellow at the University of California at Berkeley, supported by a Damon Runyan Cancer Research Foundation fellowship. Dr. Hagstrom joined the faculty of the Program in Molecular Medicine and the Program in Cell Dynamics in 2004.
Chromosome structure in gene silencing and chromosome segregation
The packaging of DNA into ordered chromosome structures has a pervasive impact on chromosome-based processes. We are using cell biology, biochemistry, and molecular genetic approaches in C. elegans to ask how proteins that organize chromosome structure mediate processes like chromosome segregation and gene silencing. These are fundamentally important questions, as defective chromosome packaging can lead to gene mis-expression and chromosome segregation errors associated with developmental defects and cancer.
Condensin complexes function in gene regulation and chromosome segregation
Condensins are conserved protein complexes that reconfigure higher-order chromosome structure. We have shown that C. elegans has conserved condensin I and condensin II complexes that promote chromosome segregation during mitosis and meiosis, plus a third, specialized condensin IDC that regulates X chromosome gene expression. Despite structural similarities and shared subunits, the condensin complexes exhibit different localization, cell cycle regulation, and functional roles. How such differences are achieved is poorly understood. We are investigating condensin specialization by defining genome-wide binding profiles and gene regulatory influences of each complex, investigating mitotic kinases that differentially regulate condensins through the cell cycle, and using proteomics to identify protein partners unique to each complex. This research will provide insight into how condensin I and II complexes of humans and other higher eukaryotes safeguard proper expression and propagation of the genome.
Chromosome architecture and RNAi-mediated gene silencing
Small RNAs regulate a variety of cellular processes, ranging from chromosome segregation to defense against transposons and viruses. We have discovered an exciting novel role for condensin proteins in RNA interference (RNAi), a process in which small RNAs negatively regulate gene expression. We showed that animals lacking condensin II can generate small silencing RNAs when exposed to double-strand RNA, but these small RNAs cannot effectively execute RNAi to reduce the transcript of the complementary gene. We find that dsRNA exposure leads to a condensin II-dependent transcription elongation block and modified chromatin at the complementary chromosomal locus. Thus, we are researching how condensin II, RNAi pathway proteins, and chromatin modifiers cooperate to alter chromatin and silence transcription during RNAi. Such research provides an opportunity both to define mechanisms by which condensins silence genes and to dissect the less-studied transcriptional aspect of RNAi.
X chromosome silencing
X chromosomes differ in number between the sexes, yet carry genes whose products are essential and must be expressed at a similar level in each sex. Chromosome-wide gene regulatory mechanisms called dosage compensation have evolved to equalize X chromosome gene expression levels between the sexes. In C. elegans, dosage compensation in the soma is carried out by condensin IDC, which binds along the two hermaphrodite X chromosomes and partially down-regulates their expression to equal that of the single X in males. In the germline, the hermaphrodite X chromosomes are silenced instead by histone methyltransferases. We discovered a new player in germline X chromosome silencing: the DRM complex of transcription factors that includes the tumor suppressor pRb. We have found that DRM and the H3K36 histone methyltransferase MES-4 counteract each other to regulate X-linked gene expression. Surprisingly, they perform this activity while bound to autosomes. Current research is directed at understanding the mechanism by which these proteins act at a distance to control chromosome-wide gene expression. Through these studies we will learn more about how these important proteins regulate genes involved in development and cancer, and how chromatin-based gene regulation can act over broad domains to regulate large sets of genes.
