Principles and design of epigenetic gene regulatory circuits
DNA sequence-specific transcription factors (TFs) are the key factors that initiate and regulate cell type-specific gene regulation. In addition, various degrees of compaction and chemical modifications of the genome have been identified to provide additional layers of regulation. Correct distribution and interpretation of such “epigenetic” modifications along the genome are highly relevant for gene regulation.
We aim to understand how epigenetic marks are specified and interpreted in a dynamic manner. One major focus is to dissect the mechanisms that guide the specificity of writers, erasers and readers of epigenetic marks to the genome. Based on genome-wide comparisons of numerous epigenetic marks, DNA sequence and transcriptional activity, several correlations and anticorrelations are apparent which suggest a context-dependent crosstalk between these features. Through applying high-throughput functional analysis and reverse engineering of epigenetic regulatory circuits, we want to dissect the underlying principles that mediate context-dependent regulation in vivo, and apply this knowledge to synthetically regulate the chromatin and transcriptional output of a cell.
Notably, we aim to characterise the minimal building blocks that determine spatiotemporal interactions between regulatory proteins and the (epi-)genome, and how these drive context-dependent regulation of biological processes in the cell. We exploit these natural building blocks to develop novel methods and tools that allow to study processes related to chromatin biology at high resolution and in a high-throughput fashion (Villaseñor et al. 2020).
Function and regulation of genome-wide DNA methylation patterns
DNA methylation is the paradigm epigenetic modification associated with transcriptional repression and required for genome function. However, the mechanisms that specify deposition and readout of this mark have not been fully understood in vivo. We have previously explored this by studying genome-wide targeting of the writers and readers of this mark (Baubec et al. Cell 2013 and Baubec et al. Nature 2015). These studies have identified how local context, such as DNA sequence composition, nucleosome positioning or gene activity can influence targeting of these factors to the genome. This knowledge allowed us to predict their binding in different cell types, and furthermore uncovered how mutations in these factors, including the ones identified in ICF or Rett Syndrome patients, result in improper establishment or readout of this relevant epigenetic mark.
Our current work aims to understand how DNA methylation is regulated through the specific activities of the de novoMethyltransferases DNMT3A and DNMT3B (Manzo et al. 2017; Mallona et al. 2020) and finally how this mark influences tissue-specific transcriptional output in healthy and diseased cells