The budding yeast Saccharomyces cerevisiae is used here as model system to understand genomic mechanisms by which genes are regulated. Changes in the disposition of regulatory factors bound across the genome will be monitored when the genome is reprogrammed. The high resolution ChIP-exo and other related assays will be used to monitor genome-wide binding events at near single-bp resolution. Heat shock will be the primary means by which the genome is rapidly reprogrammed since the immediacy of its effect largely ensures that the responding events are a direct consequence of heat shock sensing. This contrasts with other slower environmental sensing systems, where responses may include indirect effects. The general goal of this proposal is to understand gene co-regulation. The work will focus primarily on two distinct classes of genes: ribosomal protein genes (Aim 1), and heat shock induced genes (Aim 2). By defining which factors bind to responding genes and examining the how relevant factors are positionally organized spatially and temporally, and in the context of mutants that are defective in relevant functions, a deeper mechanistic understanding of gene control is obtained. Since yeast is a model for general eukaryotic systems, including human, related biological concepts and approaches developed in yeast will be applied to human cells (Aim 3). This will provide a streamlined approach towards getting at critical questions in human gene regulation, many of which have been opaque to concept development in the absence of a driving model system.

Public Health Relevance

Yeast is a simple model system for understanding biological systems including humans. Proteins that bind throughout the human genome control the genes that govern human health. Precise identification of where and how these proteins bind in the yeast and human genome and their structural organization will inform us as to the mechanics of their action.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM059055-19
Application #
9690712
Study Section
Molecular Genetics B Study Section (MGB)
Program Officer
Sledjeski, Darren D
Project Start
2000-02-01
Project End
2021-04-30
Budget Start
2019-05-01
Budget End
2020-04-30
Support Year
19
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Pennsylvania State University
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
003403953
City
University Park
State
PA
Country
United States
Zip Code
16802
García-Molinero, Varinia; García-Martínez, José; Reja, Rohit et al. (2018) The SAGA/TREX-2 subunit Sus1 binds widely to transcribed genes and affects mRNA turnover globally. Epigenetics Chromatin 11:13
Vinayachandran, Vinesh; Reja, Rohit; Rossi, Matthew J et al. (2018) Widespread and precise reprogramming of yeast protein-genome interactions in response to heat shock. Genome Res :
Yamada, Naomi; Lai, William K M; Farrell, Nina et al. (2018) Characterizing protein-DNA binding event subtypes in ChIP-exo data. Bioinformatics :
Lai, William K M; Pugh, B Franklin (2017) Understanding nucleosome dynamics and their links to gene expression and DNA replication. Nat Rev Mol Cell Biol 18:548-562
Rossi, Matthew J; Lai, William K M; Pugh, B Franklin (2017) Correspondence: DNA shape is insufficient to explain binding. Nat Commun 8:15643
Lai, William K M; Pugh, B Franklin (2017) Genome-wide uniformity of human 'open' pre-initiation complexes. Genome Res 27:15-26
Baranello, Laura; Wojtowicz, Damian; Cui, Kairong et al. (2016) RNA Polymerase II Regulates Topoisomerase 1 Activity to Favor Efficient Transcription. Cell 165:357-71
Pugh, B Franklin; Venters, Bryan J (2016) Genomic Organization of Human Transcription Initiation Complexes. PLoS One 11:e0149339
Han, G Celine; Vinayachandran, Vinesh; Bataille, Alain R et al. (2016) Genome-Wide Organization of GATA1 and TAL1 Determined at High Resolution. Mol Cell Biol 36:157-72
Jeronimo, Célia; Langelier, Marie-France; Bataille, Alain R et al. (2016) Tail and Kinase Modules Differently Regulate Core Mediator Recruitment and Function In Vivo. Mol Cell 64:455-466

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