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ATP-dependent
Chromatin Remodeling
Posttranslational
modification of histones
Histone Variant
Exchange
Histone code reading domains
Our laboratory is interested in multiprotein complexes that epigenetically regulate developmental gene expression and genome stability through chromatin
The deregulation of epigenetic mechanisms is considered as the main cause for cancer, hereditary and neurodegenerative diseases, and major efforts are undertaken by the scientific community to generate epigenomic maps of stem cells, normal and malignant tissues. Our laboratory is interested in the multiprotein complexes that 'draw' these maps by restructuring chromatin, how they can find a particular region within the enormously condensed genome, and which cascades of structural changes within chromatin are functionally interrelated.
We and others observed that certain chromatin remodeling events are common for gene regulation and genome stability control. Intriguingly, these events involve both canonical histones and their variants. To better understand the functional relationship between these fundamental epigenetic processes, our laboratory is currently pursuing the following questions:
- What are the chromatin restructuring complexes that act in the regulation of both developmental gene expression as well as genome stability control?
- How do these complexes act in such a precisely controlled spatial and temporal manner?
- What are their functional relationships?
Epigenetics and chromatin
The developmental biologist Condard H. Waddington in 1942 proposed 'Epigenetics' as a conceptual term to explain how one totipotent fertilized egg can give rise to various tissues and organs during the development (epigenesis) of an organism, although all cells are genetically identical (epigenetics=epigenesis+genetics). This model implied that genes involved in cellular differentiation processes predominantly are regulated through epigenetic mechanisms than genetic control.
Nowadays, epigenetics is used to describe processes that affect the 'readout' of an organism's genome without changing the genetic information itself ('epi', Greek for 'on top of'). The two major epigenetic mechanisms of genome regulation are structural changes in chromatin, which is universal for all eukaryotes, and DNA methylation, which is utilized by fewer organisms including humans.
Packaging of the genome into chromatin
Each human body cell contains about 2 meters of DNA that is packed into a nucleus of 2-6 micrometers. This is the equivalent of packing 3500 km of a 2mm thick thread into a tennis ball. To accomplish this dense condensation, the DNA is packed into a DNA/protein structure called chromatin. Chromatin protects the fragile genomic DNA from damage and 'unauthorized' access, but at the same time forms an obstacle for processes requiring access to the DNA such as transcription, DNA replication, recombination and repair. Thus, cells need to change the structure of chromatin in defined regions of their genome at precisely coordinated time points. Most structural changes within chromatin occur at the level of the nucleosome core particle. The nucleosome core particle is the fundamental repeating building block of chromatin and consists of 147 base pairs of DNA wrapped around two copies of each histone H2A, H2B, H3, and H4.
Multiprotein complexes change chromatin structure by three mechanisms
Cells need to transiently and reversibly generate local areas of 'open' versus 'closed' chromatin structure to access their genome. They employ three basic enzymatic mechanisms and combinations thereof to change the structure of chromatin - mainly on the level of the nucleosome. These are ATP-dependent chromatin remodeling, posttranslational modification of histones, and the incorporation of histone variants into nucleosomes. The reactions are catalyzed by multiprotein complexes that contain evolutionarily conserved subunits. These subunits can regulate the enzymatic activity, complex assembly or disassembly, complex targeting, interaction with histones, DNA, or other chromatin modifiers, etc. Not surprisingly, the majority of subunits were identified as tumor suppressors and with links to many cancers and other diseases.
Readers and writers of the histone code
In higher eukaryotes, the posttranslational modification of nucleosomes and the incorporation of histone variants are highly regulated and occur in precise temporal and spatial patterns during development. These - usually inheritable - changes help establish and maintain the developmental gene expression programs that eventually determine the identity of tissues and organs. Certain combinations of histone modifications and variant exchange reactions are closely intertwined and establish an intricately balanced 'histone code'. Imbalances in the histone code are linked to cancer, ageing, neurodegenerative and other hereditary diseases, making it enormously important for us to decipher this code.
It is clear that some complexes must be able to specifically recognize the histone modification marks that were left behind by their predecessors. Recent studies led to the identification of evolutionarily conserved modification 'reader' domains within these complexes which possess high affinity to premodified histones (see table below).
We and others observed that chromatin modifying complexes with function in both transcription and genome stability control contain several histone code 'readers' that are likely to cooperate in the precise targeting of the associated 'writers' to the sites of their activities. To this date, practically nothing is understood about the functional interaction and the subtle difference between these 'readers'. Remarkably, the 'readers's often are also tumor suppressors, suggesting that they might have crucial roles in tumorigenesis.
