Dom Helmlinger Lab

Our overall goal is to determine which principles govern the assembly of chromatin regulatory complexes and to characterize their structural organization, activities and regulation by signaling cues.

For this, we study the SAGA and TIP60 complexes, which carry histone acetylation, de-ubiquitination and histone variant deposition activities. Our work combines standard molecular, biochemical, and genetic assays with innovative genomic, proteomic, and structural biology approaches, using both fission yeast and cancer cell lines as experimental systems.

Gene regulation is crucial to generate phenotypic diversity between cells of identical genotypes, for example during cell type specification or in response to environmental changes. A critical step in gene expression is transcription, which is controlled by many distinct epigenetic regulators, such as chromatin-modifying and –remodeling complexes. Alterations of their functions have been documented in various human diseases, most notably during neurodegeneration or tumorigenesis. Several chromatin regulatory complexes function as co-activators during transcription initiation, bridging promoter-bound activators to the general transcription machinery. Co-activators have the ability to bind multiple transcription factors and thereby to coordinately regulate the expression of many genes in response to signaling cues.

Despite many studies over the past two decades, several challenges remain in our understanding of co-activator complexes. Our research is articulated around three unanswered questions:

Aim 1: How do signaling pathways control the regulatory activities of transcription co-activators?

Aim 2: How do co-activators sustain both basal transcription and the dynamic regulation of transcription in response to signaling cues?

Aim 3: What are the principles governing co-activator complex assembly and can their assembly be modulated to control their activities?

To address these issues, we combine classical molecular, cell biology, genetics, and biochemistry assays with cutting-edge transcriptomic, epigenomic, proteomic, and structural biology approaches, using both the fission yeast Schizosaccharomyces pombe and human cancer cell lines, as experimental systems.

In the presence of nutrients, particularly of a good nitrogen source, S. pombe cells grow and proliferate. In contrast, in starvation conditions, they exit the cell cycle and differentiate into a quiescent state. In this yeast, we decipher the mechanisms by which nutrient-sensing kinases control transcription and chromatin regulators. In parallel, we explore the roles of dedicated chaperones in the coordinated assembly of these factors into active multimeric complexes.

In parallel, we investigate whether similar processes contribute to control the balance between proliferation and quiescence of cancer cells. Indeed, given the high conservation of these factors, what we learn in yeast is likely to be relevant to other, ‘slower-growing’ eukaryotes. This issue is important because some cancer cells could exit quiescence, resume proliferation and cause tumor relapse. Forcing these cells to stay dormant could be an effective way of stopping tumor recurrence following conventional therapies.