We study epigenetics, specifically nucleic acid and histone modifications that influence cell fate change and maintenance. We use a broad spectrum of methods - from different variants of high-throughput sequencing, through classical biochemistry and structural biology, to large-scale data analysis. Our research is relevant to oncology, particularly to understanding hematologic malignancies in which epigenetic disruption plays an important role. 

Research Summary

Our work focuses on 2'-deoxynucleotide modifications and metabolism. We are interested in the integrity of the 2'-deoxynucleotide pool and its potential consequences for epigenetics, particularly in developmental biology and cancer biology contexts. More recently, we have also initiated projects on amino acid metabolism, again in a cancer context. 

The main biological theme of our projects is hematological malignancies. We study, among others, mixed lineage leukemia (MLL), acute myeloid leukemia with complex karyotype (CK-AML), and asparaginase treatment in acute lymphoblastic leukemia (ALL). 

Methodologically, the group uses biochemistry and structural biology, but increasingly also relies on high-throughput sequencing and animal models. This allows us to test the relevance of biochemical concepts in a more physiological setting. 

Scientific Impact

• We have contributed to the understanding of DNA modification pathways. 
• We have identified enzymes that balance or sanitize the 2'-deoxynucleotide pool. 
• We have contributed molecular insights to the biology of MLL and CK-AML. 
• In our work on CDADC1, we showed that human CDADC1 is a (d)CTP-specific deaminase. High-resolution structures explained the enzyme's substrate specificity, while genetic experiments in mice showed that loss of Cdadc1 is well tolerated, even in the absence of Dctd. 

Future Goals

We would like our work to have clinical impact in the future. For this reason, we are developing new clinical collaborations that should help connect our discoveries more closely with the biology of hematological diseases and potential practical applications. 

Collaborations

We collaborate with academic partners, including Prof. G. Xu, Prof. J. Weng, Dr. T. Jurkowski, Dr. T. Hore, Dr. C. Winata, and Dr. A. Wlodawer, as well as with industry representatives, including Dr. P. Weigele. The group is also developing clinical collaborations with Dr. K. Gawle-Krawczyk, Prof. A. Kraemer, Prof. F. Stoelzel, Dr. T. Bochtler, Prof. A. Stenzinger, Prof. O. Neumann, and Dr. D. Kazdal. 

Comment

“After many years of doing purely basic research, it would be nice to also have a practical impact,” says Prof. Matthias Bochtler. 

The team studies epigenetics, nucleic acid modifications, and 2'-deoxynucleotide metabolism, as well as their relevance to cell-fate stability and the development of hematological malignancies. The illustration presents the activity, structure, and function of vertebrate CDADC1: its activity as a (d)CTP deaminase, the structural basis of triphosphate specificity, and observations from the Cdadc1 KO mouse model.