[R01] Defining epigenetic mechanisms for embryonic patterning
Ente: Eunice Kennedy Shriver National Institute of Child Health and Human Development
Scadenza: 2031-04-30
Importo max: 348.733 EUR
Paese: US
Descrizione
PROJECT SUMMARY/ABSTRACT
Cell fate specification depends on the ability of cells to selectively activate and silence developmental gene
regulatory programs. Polycomb group (PcG) complexes maintain transcriptional repression of lineage-
inappropriate genes by depositing trimethylation on Histone H3 lysine-27 (H3K27me3) across broad
chromatin domains. Although PcG dysregulation causes multiple congenital neurodevelopmental disorders
and cancers including Weaver syndrome, Cohen-Gibson syndrome, and aggressive hematologic malignancies,
the fundamental mechanisms that govern how PcG domains are first established, spread, and remodeled
during cell fate transitions remain unresolved. Most experimental systems only allow analysis of stable
chromatin states, obscuring the transient and instructive steps of domain formation and erasure.
The early Drosophila embryo provides unique access to these dynamics. Prior to zygotic genome activation
(ZGA), H3K27me3 is absent; during ZGA, hundreds of PcG domains nucleate and catalyze spreading of
H3K27me3 over long distances with precise and reproducible kinetics. We will leverage this tractable
developmental system together with defined genetic perturbations and quantitative chromatin profiling to
determine:
Aim 1: how catalytic efficiency, allosteric feedback, and PRC1-dependend H2A ubiquitylation control
H3K27me3 spreading from Polycomb Response Elements.
Aim 2: How H3K27me3 states are rapidly reversed during neural induction through Utx demethylation and/or
H3.3 dependent nucleosome turnover, and whether Sox-B transcription factors target these processes to
neurogenic loci.
Aim 3: Whether a minimal reaction-diffusion mechanism fit to our in vivo perturbation datasets is sufficient to
reproduce the observed in vivo domain-scale propagation of H3K27me3.
Together, these studies will define the biochemical parameters and feedback architecture that set the dynamics
of PcG-mediated lineage control. By establishing a quantitative and predictive framework for H3K27me3
domain formation, this work will provide mechanistic insight directly relevant to human developmental
disorders and malignancies caused by mutations in EZH2, EED, RING1, and UTX, and will reveal generalizable
principles of chromatin-based cell fate regulation across metazoans.
Istituzione: NORTHWESTERN UNIVERSITY
PI: Shelby Alexander Blythe
Progetto: 2R01HD101563-06A1
Settori: Eunice Kennedy Shriver National Institute of Child Health and Human Development
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