Chromatin through the kaleidoscope of evolution.

Synthetic Biology | Systems Genetics | Chromatin | Transcription | Evolution

Chromatin is at the heart of eukaryotic diversity—from shaping the course of development, to responding to an ever-changing environment. I use evolutionary and synthetic molecular variation to understand the fundamental mechanisms driving chromatin function, how they shape an organism’s fate and fitness, and how we can use these insights to improve human health.

Where I’ve Been

Senior Postdoc, Frederic Berger Group, Gregor Mendel Institute, Vienna BioCenter, Vienna, Austria

PhD, Dan Jarosz Lab, Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA, USA

Key Publications

Harvey, Z.H., Stevens, K., Warnecke, T, Berger, F. 2024. Transcription elongation is dictated by single residues in the histone core domain. BioRXiv. DOI: https://doi.org/10.1101/2024.05.10.593535

The chromatin fiber is thought to pose an obstacle to transcription initiation, with chromatin remodeling and modification required to allow for efficient gene expression. However, once RNAPII transitions from initiation to elongation, it proceeds relatively unimpeded. This suggests that chromatin structure itself is insufficient to explain the relationship to transcription. In this work, we show that, rather than being an obstacle to transcription, the chromatin fiber directly encodes its transcriptional potential. Using the ancestral histone H2A variant H2A.Z as model, we demonstrate that a direct physical interaction between its core domain loop 2 with the RNAPII subunit Spt6 is sufficient to drive either activated or repressed transcriptional states. Moreover, Spt6 can read even single residue differences in H2A.Z L2, establishing that the core domain is a powerful mechanism to reshape transcription in eukaryotes.

Harvey, Z.H., Chakravarty, A.K., Futia, R.A., Jarosz, D. F., 2020. A Prion Epigenetic Switch Establishes an Active Chromatin State. Cell, 180:5, 928-940. DOI: https://doi.org/10.1016/j.cell.2020.02.014

Eukaryotes have evolved multiple synergistic mechanisms to ensure the transmission of transcriptionally repressive chromatin from one generation to the next, but whether this might also be true for activated transcriptional states was unknown. In this work, we showed that it is possible to transmit such a state both mitotically and meiotically, but that it relies on a completely different mechanism: the self-templating conformations of prion proteins. The prion in question, which we term [ESI+], can be switched on or off by cellular and environmental cues, and once activated drives heritable expression of previously silent sub-telomeric heterochromatin through interference with Rap1. [ESI+] has broad consequences on cellular fitness, giving rise to a general stress-tolerance, but at the consequence of meiotic fitness. Given that the protein(s) underlying [ESI+] are broadly conserved among eukaryotes, this work expands the known cellular repertoire for gene regulation, suggesting prion-like self-templating may be a common mechanism shaping the functional genome.

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