EPIGENETIC PROJECTSWhat is epigenetics?
Epigenetics can be broadly defined as the study of changes produced in gene expression caused by mechanisms other than changes in the underlying DNA sequence. Epigenetic phenomena are often tightly linked with gene regulation and transcriptional regulation, but they are also involved in a myriad of other cellular processes, such as alternative splicing, epigenetic memory, development, cell differentiation, or X-chromosome inactivation.
Epigenetic information can be seen as an additional layer of information on top of the genetic code. A number of distinct mechanisms contribute to epigenetic information, such as DNA methylation, nucleosome occupancy and positioning, post-translational histone modifications, or histone variants.
Some of the epigenetic information can be stably propagated through mitotic and meiotic cell divisions, and particularly the inheritance through meiosis defies Mendelian laws substantially. This transmission and inheritance is crucial for the establishment of fundamental biological mechanisms and is called epigenetic memory or epigenetic somatic inheritance.
Epigenetic memory is particularly interesting and the exact underlying mechanisms are not known. Different ideas have been formulated how this memory may be established and inherited, and one promising hypothesis is that the memory forms through transient signals that set the cell into two or more alternative regulatory states (e.g., highly methylated vs. highly acetylated regions). This idea, however, is challenged by DNA replication, because current knowledge assumes that first, nucleosomes are placed randomly between the two daughter strands whenever the cell divides and that second, newly incorporated nucleosomes are unmodified (after initial modifications that are necessary for the correct placement have been removed). Thus, on average, half of the epigenetic information is lost whenever the cell divides. Epigenetic inheritance thus entails a partial re-computation of modification patterns from incomplete information, for which different mechanisms are conceivable. A promising mechanism for this re-computation is based on positive feedback loops in nucleosome modification. Briefly, this model draws from the hypothesis that after cell division, enzymes are recruited by the parental (and often modified) nucleosomes, which then potentially re-establish the parental pattern by preferentially modifying the newly deposited unmodified nucleosomes. Indeed, some histone-modifying enzymes are known to bind to modified histones of the same type with higher affinity.
We implement this model using computer simulations to determine key parameters that affect epigenetic stability, redundancy, and efficiency of transmission.
Properties of histone modifications
Numerous findings have begun to shed light on the fundamental principals and mechanisms that underlie epigenetic phenomena. Histone modifications, for example, display a staggering variability and complexity, and they generally activate or repress transcription (sometimes even both, depending on other cellular factors). We are generally interested to better understand this variability and to identify potential properties that affect epigenetic stability and inheritance (see the project "Epigenetic inheritance" above).
For this project, we collected a large number of publicly available ChIP-Seq datasets for the genome-wide distribution of a total of 38 different histone modifications, the histone variant H2A.Z, RNA polymerase II, and the insulator binding protein CTCF. Importantly, we have data for up to five datasets in different cell lines for a particular histone modification, which allows us to quantify the variability that individual histone modifications can display.
For example, we study the domain length distributions and the redundancy of different histone modifications, because it is tempting to speculate that modifications with longer domains or higher redundancy can also be inherited more stably across generations.