Ursula Storb, M.D.

APPOINTMENTS

  • Professor Emerita, Department of Molecular Genetics and Cell Biology, Cancer Research Center, Committee on Cancer Biology, Committee on Developmental Biology, Committee on Genetics, Committee on Immunology

EDUCATION

M.D. University of Freiburg, 1960

CONTACT INFORMATION

The University of Chicago
CLSC 145B
920 East 58th Street
Chicago, Illinois 60637

stor@uchicago.edu

Phone:  (773) 702-4440

RESEARCH SUMMARY

Gene expression is controlled by activation and repression. Repression can be caused by methylation of cytosine in the sequence 5'CpG3'. 70% of CGs are methylated in mammals. Preventing DNA methylation is embryonic lethal because it results in uncontrolled gene activation. Very little is known about how methylation is targeted. The methylation modifier gene, Ssm1, discovered by our laboratory, is a candidate for encoding such a novel targeting function. When a transgene, HRD, comes under the influence of Ssm1, it is highly methylated at CGs and not expressed. Ssm1 acts early in embryonic development. It seems to direct methyl-transferases to its target genes. Only after DNA methylation does the target gene adopt an inactive chromatin state and cease to be transcribed. We have mapped Ssm1 to a small interval in the mouse genome and have used positional cloning to identify the Ssm1 gene. Ssm1encodes a KRAB-ZincFinger protein. We postulate that the Zinc fingers bind DNA sequences the embryo needs to inactivate and that the KRAB domain interacts with other proteins that cause methylation of the marked DNA sequences. The characterization of Ssm1 and the determination of its endogenous targets and effects throughout development are of major importance. It will help to understand how genes are targeted for silencing in normal development and cancer.

Another project is the somatic hypermutation (SHM) of immunoglobulin genes that encode antibodies for immunity. Antibodies are produced by B lymphocytes. When these cells encounter a foreign substance, such as bacteria or viruses, they undergo a very high rate of SHM of the expressed antibody genes. SHM is initiated by a cytidine deaminase changing cytosines into uracils. In other genes, such uracils are repaired by base excision repair. However, in antibody genes during SHM, error-prone DNA polymerases introduce more errors into all four bases (A, C, G, T). In this fashion, the affinity of the antibodies vastly increases, aiding the destruction of infectious agents or cancer cells. The molecular details of the mutation mechanism, including transcription, error prone DNA repair, and the role of chromatin are a major focus of our laboratory.


Under the control of the modifier Ssm1, the HRD transgene undergoes strain-specific DNA methylation. Bisulfite analysis shows that CpG dinucleotides are almost completely methylated (red marks) in every transgene sequence in adult B6 (black mouse) but very little in D2 (beige mouse). Mice of the D2 strain express the transgene throughout life. B6 early embryos express the transgene, but starting around day 6 of embryogenesis, B6 mice cease expression when CpGs are completely methylated and inactivating chromatin changes have taken place.

View Research Papers on PubMed