Uncovering a new role of nucleosomes in gene regulation Transcriptional factors (TFs) and nucleosomes are two major determinants for gene regulation in eukaryotic cells. Traditionally, TFs and nucleosomes are considered to be mutually exclusive. Recent studies have identified a growing list of proteins including the tumor suppressor p53 that are able to bind to nucleosomal DNA without disrupting the overall nucleosome structure. At least for these TFs, nucleosomes are no longer obstacles, and in some cases, nucleosomes can facilitate or even stabilize TF-DNA interactions. However, it was not clear if such interactions (between TFs and nucleosomes) have any biological significance. Our preliminary studies have shown that the extent of accessibility of p53 target sites in nucleosomes correlates with how p53 regulates its target genes, which highlights the importance of nucleosomes in mediating TF binding and controlling gene expression. The proposed research aims to gain full understanding of this new role of nucleosomes in gene regulation. In the Aim 1, we will focus on p53, intending to establish the link between accessibility of p53 binding sites in the context of chromatin and expression patterns of nearby genes. In the Aim 2, we will discover a comprehensive set of potential nucleosomal DNA-binding proteins in humans and model organisms. Nucleosome-TF interactions of interest will be validated by in vitro assays. At the conclusion of these studies, we will have re-defined the roles of nucleosomes in TF binding and gene regulation, developed theoretical and experimental method for testing nucleosome-TF interactions, and established a computational/experimental pipeline to identify nucleosomal DNA-binding proteins.

Public Health Relevance

Uncovering a new role of nucleosomes in gene regulation Relevance: The tumor suppressor p53 is a well-established transcriptional factor (TF) that can bind to its target sites embedded in nucleosomes. These nucleosome-TF interactions are critical for p53 to make the decision of life (i.e., cell cycle arrest) versus death (i.e., apoptosis). This project aims to elucidate this new role of nucleosomes in mediating p53 (or more generally TF) binding and controlling gene expression in higher eukaryotes.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Academic Research Enhancement Awards (AREA) (R15)
Project #
1R15GM116102-01
Application #
8957459
Study Section
Special Emphasis Panel (ZRG1-GGG-L (81))
Program Officer
Carter, Anthony D
Project Start
2015-09-01
Project End
2018-08-31
Budget Start
2015-09-01
Budget End
2018-08-31
Support Year
1
Fiscal Year
2015
Total Cost
$358,925
Indirect Cost
$113,925
Name
Rochester Institute of Technology
Department
Other Basic Sciences
Type
Schools of Arts and Sciences
DUNS #
002223642
City
Rochester
State
NY
Country
United States
Zip Code
14623
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LoVerso, Peter R; Cui, Feng (2016) Cell type-specific transcriptome profiling in mammalian brains. Front Biosci (Landmark Ed) 21:973-85
Ocampo, Josefina; Cui, Feng; Zhurkin, Victor B et al. (2016) The proto-chromatosome: A fundamental subunit of chromatin? Nucleus 7:382-7
LoVerso, Peter R; Cui, Feng (2015) A Computational Pipeline for Cross-Species Analysis of RNA-seq Data Using R and Bioconductor. Bioinform Biol Insights 9:165-74
Norouzi, Davood; Katebi, Ataur; Cui, Feng et al. (2015) Topological diversity of chromatin fibers: Interplay between nucleosome repeat length, DNA linking number and the level of transcription. AIMS Biophys 2:613-629
LoVerso, Peter R; Wachter, Christopher M; Cui, Feng (2015) Cross-species Transcriptomic Comparison of In Vitro and In Vivo Mammalian Neural Cells. Bioinform Biol Insights 9:153-64