The coordinated regulation of gene expression is a fundamental process in biology. In this proposal, we explore the role of poly (ADP-ribose) polymerase-1 (PARP-1) and its associated factors in the chromatin- dependent control of transcription in response to cellular signaling by a steroid hormone, estrogen, and a cytokine, tumor necrosis factor alpha (TNF?). PARP-1 is an abundant, chromatin-associated enzyme that catalyzes the polymerization of poly (ADP-ribose) (PAR) chains on target proteins from donor nicotinamide adenine dinucleotide (NAD+) molecules. PARP-1 plays key roles in a variety of physiological and pathological systems, including hormonal signaling, metabolism, inflammation, differentiation, adipogenesis, carcinogenesis, development, and aging. The long-term objective of these studies is to achieve a better understanding of the chromatin-dependent molecular mechanisms underlying signal-regulated transcription by PARP-1 and its associated factors. Our broad hypothesis is that the gene regulatory activities of PARP-1 are determined by: (1) the local chromatin environment (e.g., chromatin composition, histone modifications), (2) physical and functional interactions among PARP-1, transcription factors (e.g., ER?, NF-?B), histone-modifying coregulators, and components of chromatin, (3) the targets of PARP-1 enzymatic activity, and (4) the availability of NAD+ in the nucleus. We will test this hypothesis as it relates to estrogen- and TNF?-dependent gene regulation by using an integrated approach that combines a complementary set of tools from biochemistry, molecular biology, cell biology, chemical biology, and genomics. Specifically, we will determine (1) the chromatin-dependent molecular mechanisms of PARP-1 localization and activity at target gene promoters, including the role of the histone variants H2A.Z and H3.3;(2) the effects of PARP-1-dependent site- specific PARylation on the activity and function of chromatin-regulating proteins, including the histone demethylase KDM5B and the histone methyltransferase Ezh2;and (3) the mechanisms by which NAD+ production by the nuclear NAD+ synthase nicotinamide mononucleotide adenylyltransferase-1 (NMNAT-1) regulates PARP-1 enzymatic activity at target gene promoters. Collectively, these studies will provide new insights into the molecular mechanisms of PARP-1's gene regulatory activities in the context of chromatin, especially in relation to estrogen and TNF? signaling, and nuclear NAD+ biosynthesis and availability. Given the important role of PARP-1 in human disease, as well as its potential """"""""drugability"""""""", our studies could lead to new ways to exploit these factors as therapeutic targets.
PARP-1 is an abundant nuclear enzyme that controls gene expression programs in a variety of signaling- and stress-related biological responses, including hormonal signaling, metabolism, inflammation, differentiation, adipogenesis, carcinogenesis, development, and aging. PARP-1 enzymatic activity can be targeted through chemical inhibition, and PARP inhibitors have shown promise in clinical trials for various cancers and inflammation-related diseases. Our proposed studies will shed new light on the molecular mechanisms of signal-dependent gene regulation by PARP-1 in key biological systems and may suggest better ways to target PARP-1 to prevent, diagnose, and treat human diseases.
|Ryu, Keun Woo; Nandu, Tulip; Kim, Jiyeon et al. (2018) Metabolic regulation of transcription through compartmentalized NAD+ biosynthesis. Science 360:|
|Willcockson, Alexandra R; Nandu, Tulip; Liu, Cheuk-Lun et al. (2018) Transcriptome signature identifies distinct cervical pathways induced in lipopolysaccharide-mediated preterm birth. Biol Reprod 98:408-421|
|Lin, Ken Y; Kraus, W Lee (2017) PARP Inhibitors for Cancer Therapy. Cell 169:183|
|Gupte, Rebecca; Liu, Ziying; Kraus, W Lee (2017) PARPs and ADP-ribosylation: recent advances linking molecular functions to biological outcomes. Genes Dev 31:101-126|
|Liu, Ziying; Kraus, W Lee (2017) Catalytic-Independent Functions of PARP-1 Determine Sox2 Pioneer Activity at Intractable Genomic Loci. Mol Cell 65:589-603.e9|
|Luo, Xin; Ryu, Keun Woo; Kim, Dae-Seok et al. (2017) PARP-1 Controls the Adipogenic Transcriptional Program by PARylating C/EBP? and Modulating Its Transcriptional Activity. Mol Cell 65:260-271|
|Gibson, Bryan A; Zhang, Yajie; Jiang, Hong et al. (2016) Chemical genetic discovery of PARP targets reveals a role for PARP-1 in transcription elongation. Science 353:45-50|
|Ryu, Keun Woo; Kim, Dae-Seok; Kraus, W Lee (2015) New facets in the regulation of gene expression by ADP-ribosylation and poly(ADP-ribose) polymerases. Chem Rev 115:2453-81|
|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|
|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|
Showing the most recent 10 out of 32 publications