Laboratory Funding

ProjectYearProject TitleContact PI/Project
GM1257221GENOME-WIDE STRUCTURAL ORGANIZATION OF PROTEINS WITHIN HUMAN GENE REGULATORY COMPLEXESMahony, Shaun &
Pugh, Frank
ABSTRACT: The DNA sequence of the human genome informs us as to the composition of proteins that make up healthy cells, but also altered compositions that create diseased cells. How protein production is controlled through the regulation of the genes that encode them is of critical importance for healthy and diseased cells. Knowing precisely where gene regulatory proteins bind, and are organized throughout the genome, including their interactions with each other, informs us as to how genes are regulated and mis-regulated. Since there are potentially thousands of different kinds of regulatory proteins and thousands of different kinds of human cell types and environmental responses that are a product of various subsets of regulatory proteins, the entire “universe” of gene regulatory events is quite substantial and consequently, quite costly to identify. A subset of these events will likely be informative or diagnostic of diseases states. Therefore, an important goal is to define informative interactions using cost-enabling, high accuracy, and robust genome-wide assays.
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ProjectYearProject TitleContact PI/Project
ES01376812PROMOTER REGULATION IN RESPONSE TO ENVIRONMENTAL STRESSPUGH, B FRANKLIN
ABSTRACT: The regulation of eukaryotic genes involves many hundreds of proteins. How they work together at the many thousands of genes that comprise a genome is not known. In order to obtain a comprehensive understanding of how all genes are regulated, we need to know the precise spatial organization, structure, and occupancy levels of all involved proteins. We have developed a genome-wide assay, called ChIP-exo, to measure these aspects of genome regulation, and now propose to develop a higher-throughput version of the assay, and apply it to the mapping of hundreds of genome-binding proteins (aim 1). The goal of aim 2 will be to create a user-friendly, quickly-navigable, platform to execute scripts on ChIP-exo and related data, using our established pipeline. Public use utility of the ChIP-exo datasets will be enhanced with a dedicated platform.
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LINK TO PUBLICATION RESULTS


ProjectYearProject TitleContact PI/ Project Leader
GM05905518GENOME-WIDE REGULATION OF THE TATA BINDING PROTEINPUGH, B FRANKLIN
ABSTRACT: Human health is highly dependent upon proper gene expression. Understanding how genes are regulated is critical in our understanding how mis-regulation leads to diseases. One major point where genes are regulated is during the assembly of the transcription machinery. This project is focused on understanding the molecular events that govern the assembly of the transcription machinery at promoters.
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LINK TO PUBLICATIONS


ProjectYearProject TitleContact PI/Project
HG00416011HIGH RESOLUTION MAPPING OF FUNCTIONAL ELEMENTS IN THE YEAST GENOMEPUGH, B FRANKLIN
ABSTRACT: Eukaryotic DNA is packaged into chromatin, and this chromatin has a well-defined organization. Chromatin is composed of nucleosome building blocks, whose positioning along the DNA dictates the accessibility of gene regulatory elements, and ultimately the expression levels of genes. Nucleosomes occur in regular repeating intervals on genes. These arrays are highly regulated through many mechanisms including: post- translational modifications, deposition and eviction that are facilitated by chaperones, and re-positioning facilitated by chromatin remodeling complexes. We propose to further our understanding of nucleosomal arrays on a genomic scale.
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LINK TO PUBLICATIONS


Patent NumberPatent TitlePatent OwnerPrimary Agency
8367334Methods, systems and kits for detecting protein-nucleic acid interactionsPENNSYLVANIA STATE UNIVERSITYNIH


ProjectYearProject TitleContact PI/Project
GM12572202Genome-wide structural organization of proteins within human gene regulatory complexesMahony, Shaun & PUGH, B FRANKLIN
ABSTRACT: The DNA sequence of the human genome informs us as to the composition of proteins that make up healthy cells, but also altered compositions that create diseased cells. How protein production is controlled through the regulation of the genes that encode them is of critical importance for healthy and diseased cells. Knowing precisely where gene regulatory proteins bind, and are organized throughout the genome, including their interactions with each other, informs us as to how genes are regulated and mis-regulated. Since there are potentially thousands of different kinds of regulatory proteins and thousands of different kinds of human cell types and environmental responses that are a product of various subsets of regulatory proteins, the entire ?universe? of gene regulatory events is quite substantial and consequently, quite costly to identify. A subset of these events will likely be informative or diagnostic of diseases states. Therefore, an important goal is to define informative interactions using cost-enabling, high accuracy, and robust genome-wide assays. To this end, ChIP-exo was developed to map the genomic binding locations of gene regulatory proteins at near-single base pair resolution. This assay will be applied, in high throughput, to determine the genome-wide positional organization of factors within protein-DNA complexes, like enhanceosomes. By broadly mapping the various classes of proteins that constitute much of the regulated epigenome, general rules about enhancer and repressor complex organization will be deduced.
Aim 1 involves collecting genome-wide ChIP-exo data in human cell lines for a wide variety of protein-DNA complexes.
Aim 2 will develop and implement computational approaches towards pattern recognition and data distillation in ChIP-exo datasets. The results are expected to provide structural insights into macromolecular protein complex assembly on a genomic scale, and in various cell types and conditions.


ProjectYearProject TitleContact PI/Project
GM12559201Eukaryotic Gene Regulation (EGR) Predoctoral Training ProgramPUGH, B FRANKLIN
ABSTRACT: The Penn State Eukaryotic Gene Regulation (EGR) Predoctoral Training Program will train a future generation of scientists in experimental, molecular and computational sciences applied towards understanding mechanisms of eukaryotic gene regulation. The training program will build upon established graduate programs in biochemistry, molecular, cellular and developmental biology, bioinformatics and genomics. The goals of the EGR program are consistent with the Cellular, Biochemical and Molecular Sciences (CMB) program at National Institute of General Medicine. The program aims to cultivate interdisciplinary study and the training of new scientists pertaining to biological problems and cellular and molecular sciences to advance science and improve health. Nearly all aspects of biology and human disease are rooted in gene regulation. Our knowledge and abilities to understand, control, and rectify gene expression and mis-expression is fundamental to the basic knowledge cells and to the basic knowledge of medicine. A recent report from the American Cancer Society finds that we are winning the war on cancer in part because of our understanding of fundamental mechanisms of gene control. However, it is also clear that we must keep up the fight. This fight will require scientists cross-trained in experimental and computational sciences. The proposed EGR training program will train a diverse cohort of student-scientists to have critical expertise in biophysics, biochemistry, molecular biology, genetics, computational biology, and statistics to address fundamental questions in gene regulation. The program will be anchored within the Center for Eukaryotic Gene Regulation (CEGR), which has been chartered to these principles for over 20 years. Penn State?s CEGR has a long-standing reputation for producing outstanding science. This training program will connect and further develop five established graduate programs: Biochemistry and Molecular Biology (BMMB), Chemistry (CHEM), Chemical Engineering (CHE), Molecular Cellular and Integrative Biosciences (MCIBS), and Bioinformatics and Genomics (MCIBS-BG). Combining NIH and Penn State support, the EGR program plans to train a minimum of 13 predoctoral students over a period of five years. Each trainee will be supported for the two years of their training (year 2 and 3) while receiving foundational training in EGR. Trainees will gain a thorough understanding of the scientific process, responsible conduct in science, fluency in innovative research methodologies, ability to utilize genomics and statistical tools in advancing genome-wide experimental approaches, excellence in cross-disciplinary communication, and leadership in cross-disciplinary research teams.