Every cell in our body contains the same genome, yet different cell types express distinct sets of genes. Understanding how the information encoded in DNA is interpreted to establish and maintain these gene expression programs remains one of the central challenges in biology.

Our research seeks to uncover the molecular mechanisms that connect transcription factors, chromatin regulation, and RNA metabolism. We are particularly interested in whether and how sequence-specific transcription factors recruit chromatin remodeling or RNA-processing machineries to specific genomic loci, thereby determining when genes are activated, repressed, or permanently silenced. By combining mechanistic studies with systematic resource generation, we aim to reveal the molecular logic that underlies gene regulation in eukaryotic cells.

We integrate molecular biology, genetics, genomics, quantitative proteomics, biochemistry, and computational biology to investigate gene regulation across multiple scales, from individual molecular interactions to genome-wide regulatory networks.

RNA and chromatin: establishing fundamental principles

Our work has contributed to several conceptual advances in understanding how RNA regulates chromatin. Using fission yeast as a model system, we demonstrated that RNA interference (RNAi) acts on nascent transcripts to direct heterochromatin formation, providing one of the first mechanistic frameworks for RNA-guided epigenetic regulation. We subsequently uncovered mechanisms that restrict heterochromatin formation and its inheritance. Our studies established RNA as an integral component of chromatin regulation and laid the foundation for our current interest in the interplay between chromatin and RNA during transcription.

From chromatin regulation to co-transcriptional gene regulation

Our work on RNAi-guided chromatin regulation naturally led us to ask whether RNA-processing machineries have broader functions in gene regulation. Our current research explores whether transcription factors recruit RNA-processing factors to chromatin and how these interactions influence transcriptional output while RNA is still being synthesized . We refer to this emerging research direction as co-transcriptional gene regulation, which seeks to understand how chromatin regulation and RNA metabolism are integrated at the site of transcription.

One major line of research investigates the ChAHP chromatin remodeling complexes, which we discovered as modular assemblies that combine sequence-specific DNA recognition with ATP-dependent chromatin remodeling. These complexes regulate retrotransposons, shape chromatin architecture, and modulate transcription factor binding. More recently, we demonstrated that closely related ChAHP complexes employ fundamentally different recruitment strategies, illustrating how evolution has adapted common molecular building blocks to control distinct genomic targets.

A second major focus is the systematic characterization of transcription factor regulatory networks. Rather than studying transcription factors individually, we are building comprehensive experimental resources that allow their functions to be investigated at genome-wide scale. We have generated near-complete collections of endogenously tagged transcription factors in both fission yeast and mouse embryonic stem cells. By combining these resources with quantitative interaction proteomics, chromatin profiling, and functional genomics we aim to define the regulatory complexes assembled by individual transcription factors.

Our vision

Our long-term goal is to uncover the molecular principles that govern gene regulation and to understand how gene expression programs are established, maintained, and altered during development, physiology, and disease. By integrating systematic resource generation with detailed mechanistic studies, we aim to reveal how gene regulatory networks are organized and how they collectively shape genome function.

Contact
Marc Bühler