Chromatin Research in the Strahl Lab
Research Background
All life is guided by, and receives instructions through, chromatin. Chromatin represents the intricate union of the genome and a myriad of proteins that regulate gene expression, DNA repair, and replication. The histone components of chromatin are among the most ancient and evolutionarily conserved proteins, highlighting their fundamental importance to chromatin organization and genome function.
Although significant progress has been made in identifying the machinery that regulates chromatin, we still lack a precise understanding of the molecular mechanisms by which these machines operate. Additionally, we do not fully understand how or why dysregulation of the chromatin machinery or histones themselves causes a great many human diseases. These knowledge gaps drive the direction of our research program, namely, defining the elemental mechanisms by which accurate, and faulty, chromatin function occurs. To achieve this, we use yeast and mammalian cell systems, employing genetic, biochemical, proteomic, and genomic techniques. We follow wherever the science takes us, and we like to ask the big questions, which together has compelled us at times to branch out into new areas such as DNA repair, replication, and metabolism.
Our Research Areas
Defining how histone
modifying enzymes and chaperones contribute to chromatin organization and gene transcription
Poorly understood are the details by which histone chaperones and histone modifications orchestrate gene transcription events. We have made key contributions to answering questions in this area by defining how histone-modifying enzymes, e.g., Set1, Set2, Rpd3S, Bre1-Rad6, and the Spt6-Spn1 histone chaperone, function in chromatin-based gene transcription. We are continuing to investigate these and other transcription factors and remodelers to explain how they regulate nucleosome disassembly/reassembly and maintain the fidelity of gene transcription.
Uncovering the role
of histone modifications and readers in metabolic gene transcription
New histone modification types (e.g., crotonylation) and histone reader modules (e.g., YEATS domains) have been discovered, but their functions are largely unknown. We have made significant advances in this area by determining how the YEATS domain-containing Taf14, and its reading of histone crotonylation, represses metabolic genes during the yeast metabolic cycle (YMC). The YMC represents an unprecedented opportunity to define how metabolic flux and a dynamically changing chromatin environment precisely control oscillating gene transcription programs required for cell survival. Some of our current studies are focused on the precise molecular mechanism of Taf14’s control of transcription. In addition, we are examining the functions of other YEATS-containing chromatin regulators and other recently described reader domains such as the ZZ domain.
Defining the rules
by which chromatin regulators engage nucleosomes to regulate chromatin biology
Despite considerable information regarding reader domain-histone modification interactions, there is a substantial gap concerning how chromatin-associated proteins recognize these modifications in the context of nucleosomes and how “paired” domains interpret the Histone Code. We are defining the binding preferences of reader domains and how these proteins achieve multivalent interactions in chromatin that dictate their functions. Defining these binding events has significant implication for diseases caused by dysregulated histone modification. Some examples include defining the combinatorial readout of histones by UHRF1 that promotes DNMT1-directeed DNA methylation maintenance, Rpd3S that prevents spurious transcription during gene transcription, and PBRM1 of the PBAF remodeling complex to control gene transcription. Other multi-domain chromatin reader modules are currently under investigation.
