Professor - Emeritus
Universitaet Freiburg, Germany, M.D.
Gene expression is controlled by activation and repression. Repression can be caused by methylation of cytosine in the sequence 5'CpG3'. 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, 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 directs 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 identified the Ssm1 gene by positional cloning. It encodes a KRAB-zinc finger protein. The characterization of Ssm1 and the determination of its endogenous targets and effects throughout development 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 antigen, such as bacterial or viral proteins, they undergo a very high rate of mutation of the expressed antibody genes. Beneficial mutations that confer higher antibody affinity accumulate. SHM is initiated by a cytidine deaminase changing cytosines into uracils. Normally, such uracils are repaired efficiently. However, 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 can increase vastly, 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.