Chromatin Biology

Our DNA is packaged tightly into chromosomes and squeezed into a tiny nucleus. To achieve this, DNA is wrapped around unique proteins called histones, and the resulting DNA-protein complex is called chromatin. Histones are enzymatically modified with acetyl, methyl, or phosphate groups, for example. Today, we know many chemical modifications on chromatin, some of which are known to play essential roles in replication, transcription, chromatin compaction, and DNA damage repair. A large number of these marks serve as interaction hubs for many nuclear proteins and provide critical structural features for protein recruitment. Hundreds of specialized proteins bind those modifications. These reader proteins and chemical modifications, in turn, influence the protein makeup of the chromatin of each cell type of our body. Importantly, the absence and wrong placement of many chromatin modifications are associated with numerous diseases. Therefore, understanding how the chemical code influences the organization and protein composition of chromatin has become a central focus of biomedical research.

Today 22 types of histone modifications have been described. With eight modifiable amino acid residues at about 138 positions on five canonical histone variants, more than 550 possible histone modifications can occur. Several of these chemical marks can coexist on the same nucleosome resulting in an immense theoretical number of combinatorial possibilities. To date, only a few examples of new combinatorial chromatin states are known. However, these results open the exciting prospect for more combinatorial options in mammalian cells.

Our team will combine experimental and computational approaches to answer the following fundamental questions in a quantitative and comprehensive manner:

• Are more combinatorial possibilities existing on the same nucleosome with relevant biological functions?

• If so, do they occur in all cell types, or are there lineage- or even disease-specific combinations?

We plan to use our robust and quantitative chromatin-proteomics approach to explore large combinatorial possibilities at single-nucleosome resolution (see figure below) in several cell types and functionally characterize novel examples. By expanding our method to cancer cells, we will elucidate potential combinatorial chromatin modifications on single nucleosomes. Identifying cancer-specific combinatorial chromatin states could serve as promising biomarkers for cancer diagnosis.