Cellular identity is controlled by the selective expression of genes, a process determined by regulation of the "open" and "closed" states of chromatin-the complex of DNA and histone proteins. Histone post-translational modifications (PTMs) can alter the biophysical properties of chromatin and also selectively recruit o eject histone-binding proteins or "readers", thereby regulating biological processes. Among the diverse substrate options for histone-modification, the highly charged nature of phosphorylation bears great potential to alter histone-histone and histone-"reader" molecular interactions. Indeed, paralleling many upstream kinase pathways, "signaling to chromatin" through histone phosphorylation serves as a rapid, reversible, and selective mechanism for the interpretation of signaling inputs leading to chromatin processes including control of cell cycle (Aim 1), rapid induction of transcription (Aim 2), and chromati structure, histone variant regulation, and oncogenesis (Aim 3). However, numerous fundamental issues concerning histone phosphorylation and its participation in chromatin processes remain unanswered.
In Aims 1 and 2, we will test the hypothesis that diverse functions of histone phosphorylation-with a focus on transcription and cell cycl regulated processes-are defined and controlled by their association with other combinatorial histone modifications and the selective recruitment or ejection of "readers". We propose an ambitious research plan, with a high likelihood of success and supported by preliminary findings and world class collaborators. We will assess how histone phosphorylation, acting together with other histone PTMs, can serve to instruct diverse functions including cell cycle regulation and activation of transcription.
In aim 3, we propose the study of phosphorylation at histone variant-specific residues as a mechanism for signaling to chromatin at select genomic localizations, with functional consequences mediated by altered chromatin structure, nucleosome stability, and the binding of specific "readers". Additionally, we propose to study oncogenic histone mutations, flanking key phosphorylation residues, and their disruptive effects on histone phosphorylation regulated processes that may drive oncogenesis, including dysregulated cell cycle and genome instability. Here, we embrace the complexity of histone encoded information, employing novel and cutting-edge techniques together with our expertise in chromatin biology to better understand the diverse functions of histone phosphorylation. The ambition of this research is the discovery and characterization of new regulatory processes and potentially "druggable" "readers" downstream of histone phosphorylation in the context of development, inflammatory transcription responses, regulation of the cell cycle, and oncogenesis with extreme relevance to human health and disease.

Public Health Relevance

Diverse cell types are controlled by the selective regulation of genes encoded by DNA, which is packaged by histone proteins. Histone protein phosphorylation can control the selective regulation of DNA, thereby altering cell features during processes that include cancer growth, immune responses, and development.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Molecular Genetics B Study Section (MGB)
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Carter, Anthony D
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Rockefeller University
Other Domestic Higher Education
New York
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