Robert Schneider: Chromatin Dynamics and Epigenetics

We are interested in the following five main questions:

Linker histone H1 modifications and variants

The 5th histone, the linker histone H1 has an important function in establishing and maintaining higher order chromatin structures. Like the core histones, it can be highly covalently modified, however very little is known about the function of H1 modifications. We are studying the functions of H1 modifications, are identifying the modifying enzymes and unravelling their role in development and disease processes.

In addition to covalent modification, histone variants can regulate chromatin dependent processes. In mammalian cells up to 11 H1 variants can be found. The current knowledge regarding the function and expression of these H1 variants is very limited. Our aim is to systematically investigate and understand the biological function of H1 variants, particularly their role in cellular reprogramming, stem cell biology and neuronal development. This research has direct implications for cellular plasticity and targeted cell reprogramming. 

Together, our research on H1 will enable us to revisit the role of the linker histone from a mere structural chromatin component towards more specific functions.

Staining of DNA (blue), histone H1 (red) and Oct 4 (green) in future germ cells. Source: IFE

Staining of DNA (blue), histone H1 (red) and Oct 4 (green) in future germ cells. Source: IFE

New sites and new types of histone modifications

Covalent modifications of histones regulate chromatin structure and function, as well as act as carriers of epigenetic information. The major challenges to address are to understand how these modifications are translated into concrete changes in gene expression and how the environment impacts histone modifications. The set of characterized histone modifications is still not complete and by studying new modifications we can identify novel mechanisms regulating chromatin function. 

In addition to the histone tails, the central part of the nucleosome can also be modified. We have demonstrated a causative function for modifications within the core of the nucleosome in transcriptional regulation and established these as major regulators of chromatin function, addressing key questions about the causality of histone modifications. 

We have recently discovered new types and sites of histone modifications. Currently we are performing systematic studies in mouse and human cells, including genome-wide analysis and in vitro approaches such as chromatin reconstitutions, to unravel how these novel modifications mechanistically regulate chromatin function and how they couple chromatin structure with the environment and disease.

Modifiable residues on the lateral surface of the histone octamers that are close to the DNA. Source: IFE

Modifiable residues on the lateral surface of the histone octamers that are close to the DNA. Source: IFE

Linking chromatin states with metabolism

Recently, it has become evident that the epigenome has the capacity to link the genome with the cellular and extracellular environment. The epigenome can integrate and store signaling information, as well as environmental impacts, and in turn regulate transcriptional responses. For example, histone modifying enzymes (methytransferases, demethylases, or deacetylases) use metabolic intermediates as co-factors and thereby can couple chromatin architecture with the metabolic state. 

We are using our expertise on novel histone modifications to understand how the metabolic state of a cell impacts on chromatin function and thereby link chromatin structure with metabolism, an emerging field called metaboloepigenomics.  By identifying novel pathways and novel histone modifications linking metabolism with chromatin architecture, our long term goal is to be able to revert chromatin dysfunction in diseases where metabolic regulation is impaired.

Metabolic intermediates serve as co-factors for histone modifiers and can regulate their activity. Source: IFE

Metabolic intermediates serve as co-factors for histone modifiers and can regulate their activity. Source: IFE

Epigenetics inheritance in single cells

Currently, most studies in the epigenetics and chromatin fields have used cell populations containing high cell numbers. This approach has a major shortcoming, because averaging populations can mask differences between individual cells. Thus, it is now a key challenge for biologists to understand how chromatin regulates cellular processes at a single cell level and how these “epigenetic” states are inherited to cellular progenies.

To study individual cells, we are using a novel microfluidics system where we can trap individual cells within micro-channels in microfluidics chambers. With this setup, we can study the inheritance of transcriptional states over multiple generations. Currently we are focusing on the “memory” of gene expression programs, in particular the chromatin mechanism that allows genes to “remember” their previous transcriptional state.

Our aims are (i) to identify the chromatin based mechanisms that underlie the memory of transcriptional states, (ii) to generate comprehensive data to model stochasticity of gene expression and its inheritance to subsequent generations and (iii) the effects of epigenetic modifiers and histone modifications in individual cells on gene expression and chromatin states over multiple generations.

Overall, our unique setup will allow us to tackle key questions about epigenetic memory in single cells and epigenetic inheritance to their progenies. It will also be important for understanding how cells adapt their response to repeated stimuli and the role of chromatin in the memory of transcriptional states.

Microfluidics chip setup that allows segmentation, mapping and pedigree analysis (top) and single cell linage tracing (bottom). Source: Gilles Charvin (IGBMC) and IFE

Microfluidics chip setup that allows segmentation, mapping and pedigree analysis (top) and single cell linage tracing (bottom). Source: Gilles Charvin (IGBMC) and IFE

Readout of chromatin modification states by epigenetic effectors - Till Bartke

Epigenetic information is “read” by epigenetic effector molecules that recognise DNA and histone modifications through specialised binding domains in order to regulate chromatin function and to orchestrate subsequent biological events such as transcription, DNA replication or DNA repair. It has become apparent in recent years that DNA and histone modifications do not act in isolation but form combinatorial modification signatures that define the functional state of the underlying chromatin. For example, promoters, enhancers, transcribed genes and silent heterochromatin are all marked by characteristic sets of chromatin modifications which are now widely used to annotate the genome.

We combine chemical biology, biochemical, and proteomic approaches with cell biology and computational analyses to unravel how epigenetic effector molecules can read DNA and histone modification patterns and how they recognise different chromatin modification states. Our goal is to decipher the “epigenetic code” by identifying epigenetic reader molecules that can integrate information from multiple chromatin modifications and to understand how these factors operate at the molecular level both in healthy and pathological conditions. This knowledge will provide important new insights into the mechanisms of chromatin regulation and will aid in the development of epigenetic drugs for the treatment of diseases caused by defects in the epigenetic machinery.

Source: IFE

Source: IFE

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