Estrogens play key roles in the normal development and function of reproductive organs, mammary glands, bone, heart, vasculature, adipose, and central nervous system, as well as common dysfunctions of the same tissues. The long-term objective of these studies is to achieve a better understanding of the mechanisms by which liganded ERs control global patterns of gene expression to regulate cellular physiology. Our overall hypothesis is that biological context will play a key role in determining the nature and extent of estrogen-dependent transcriptional responses, and that estrogen responses will differ from the responses to other signaling pathways. In this proposal, we will use a unique, sensitive, powerful, and comprehensive new genomic approach for transcriptional profiling called Global nuclear Run-On and Sequencing (GRO-seq), which is superbly suited to the analysis of specific transcriptional mechanisms that cannot be addressed by other means. In the studies described herein, we will use GRO-seq in combination with other genomic, computational, and gene-specific assays, to elucidate the molecular and genomic mechanisms underlying the immediate and primary effects (i.e., minutes, not hours) of estrogen on the transcriptomes of normal and cancerous cells, including effects on non-coding transcripts. Specifically, we will: (1) determine the functional relationships between estrogen signaling pathways, ERa binding events, and estrogen-dependent transcriptional outcomes, (2) determine the mechanisms of regulation and functional roles of non-coding estrogen-regulated transcripts, with an emphasis on antisense transcripts, and (3) define and analyze the immediate/primary estrogen-regulated transcriptome in a variety of biological systems. These studies will exploit the power of GRO-seq to address fundamental molecular mechanisms and will reveal new mechanistic insights that will change the way we think about estrogen signaling. The increased understanding of estrogen signaling gained from these studies will aid in finding better ways to prevent, diagnose, and treat estrogen-related diseases. In addition, since ERs represent prototypical signal-regulated transcription factors, the study of ER function using GRO-seq will shed light on gene regulation by other transcription factors and suggest new ways to study their biology.

Public Health Relevance

Estrogens play key roles in the normal development and function of reproductive organs, mammary glands, bone, heart, vasculature, adipose, and central nervous system, as well as common dysfunctions of the same tissues. In this proposal, we will use a powerful new genomic approach, called GRO-seq, to elucidate the molecular and genomic mechanisms underlying the immediate and primary effects of estrogen on the transcriptomes of normal and cancerous cells, including effects on unannotated and non-coding transcripts. The increased understanding of estrogen signaling gained from these studies will aid in finding better ways to prevent, diagnose, and treat estrogen-related diseases, as well as shed light on gene regulation by other transcription factors and suggest new ways to study their biology.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK058110-13
Application #
8334694
Study Section
Molecular and Cellular Endocrinology Study Section (MCE)
Program Officer
Margolis, Ronald N
Project Start
2000-09-15
Project End
2016-08-31
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
13
Fiscal Year
2012
Total Cost
$433,673
Indirect Cost
$158,843
Name
University of Texas Sw Medical Center Dallas
Department
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
Doiguchi, Masamichi; Nakagawa, Takeya; Imamura, Yuko et al. (2016) SMARCAD1 is an ATP-dependent stimulator of nucleosomal H2A acetylation via CBP, resulting in transcriptional regulation. Sci Rep 6:20179
Liu, Xiuli; Kraus, W Lee; Bai, Xiaoying (2015) Ready, pause, go: regulation of RNA polymerase II pausing and release by cellular signaling pathways. Trends Biochem Sci 40:516-25
Sun, Miao; Gadad, Shrikanth S; Kim, Dae-Seok et al. (2015) Discovery, Annotation, and Functional Analysis of Long Noncoding RNAs Controlling Cell-Cycle Gene Expression and Proliferation in Breast Cancer Cells. Mol Cell 59:698-711
Franco, Hector L; Nagari, Anusha; Kraus, W Lee (2015) TNFα signaling exposes latent estrogen receptor binding sites to alter the breast cancer cell transcriptome. Mol Cell 58:21-34
Chae, Minho; Danko, Charles G; Kraus, W Lee (2015) groHMM: a computational tool for identifying unannotated and cell type-specific transcription units from global run-on sequencing data. BMC Bioinformatics 16:222
Sun, Miao; Kraus, W Lee (2015) From discovery to function: the expanding roles of long noncoding RNAs in physiology and disease. Endocr Rev 36:25-64
Danko, Charles G; Hyland, Stephanie L; Core, Leighton J et al. (2015) Identification of active transcriptional regulatory elements from GRO-seq data. Nat Methods 12:433-8
Winans, Bethany; Nagari, Anusha; Chae, Minho et al. (2015) Linking the aryl hydrocarbon receptor with altered DNA methylation patterns and developmentally induced aberrant antiviral CD8+ T cell responses. J Immunol 194:4446-57
Allen, Mary Ann; Andrysik, Zdenek; Dengler, Veronica L et al. (2014) Global analysis of p53-regulated transcription identifies its direct targets and unexpected regulatory mechanisms. Elife 3:e02200
Hussey, Kristine M; Chen, Hongshan; Yang, Christine et al. (2014) The histone variant MacroH2A1 regulates target gene expression in part by recruiting the transcriptional coregulator PELP1. Mol Cell Biol 34:2437-49

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