@article{9ec76efe57f14a44a4da70cb04e8e5b7,
title = "Nuclear ADP-ribosylation drives IFNγ-dependent STAT1α enhancer formation in macrophages",
abstract = "STAT1α is a key transcription factor driving pro-inflammatory responses in macrophages. We found that the interferon gamma (IFNγ)-regulated transcriptional program in macrophages is controlled by ADP-ribosylation (ADPRylation) of STAT1α, a post-translational modification resulting in the site-specific covalent attachment of ADP-ribose moieties. PARP-1, the major nuclear poly(ADP-ribose) polymerase (PARP), supports IFNγ-stimulated enhancer formation by regulating the genome-wide binding and IFNγ-dependent transcriptional activation of STAT1α. It does so by ADPRylating STAT1α on specific residues in its DNA-binding domain (DBD) and transcription activation (TA) domain. ADPRylation of the DBD controls STAT1α binding to its cognate DNA elements, whereas ADPRylation of the TA domain regulates enhancer activation by modulating STAT1α phosphorylation and p300 acetyltransferase activity. Loss of ADPRylation at either site leads to diminished IFNγ-dependent transcription and downstream pro-inflammatory responses. We conclude that PARP-1-mediated ADPRylation of STAT1α drives distinct enhancer activation mechanisms and is a critical regulator of inflammatory responses in macrophages.",
author = "Rebecca Gupte and Tulip Nandu and Kraus, {W. Lee}",
note = "Funding Information: We thank Dr. Cristel Camacho and Aarin Jones for critical comments on this manuscript. We also like to acknowledge and thank the following: Venkat Malladi for assistance with analysis of the sequencing data, Aishwarya Sunderesan for assistance with analysis of mass spectrometry data, Dr. Sridevi Challa for help with microscopy, Dr. Rossella Titone and Dr. Danielle M. Robertson for help with the Seahorse assays, and Dr. Inez Rogatsky (Hospital for Special Surgery, New York, NY) for providing the immortalized mouse bone marrow-derived macrophages (iBMDMs). We acknowledge and thank the following UT Southwestern core facilities: Live Cell Imaging Core for microscopy support (Dr. Katherine Luby-Phelps), Next Generation Sequencing Core for deep sequencing services (Vanessa Schmid) and Proteomics Core for the mass spectrometry (Dr. Andrew Lemoff). This project was also supported by the Protein and Monoclonal Antibody Production Shared Resource at Baylor College of Medicine (with funding from NIH Cancer Center Support Grant P30 CA125123). This work was supported by a grant from the NIH/National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (R01 DK058110) and funds from the Cecil H. and Ida Green Center for Reproductive Biology Sciences Endowment to W.L.K., and by an American Heart Association postdoctoral fellowship to R.G. Publisher Copyright: {\textcopyright} 2021, The Author(s).",
year = "2021",
month = dec,
day = "1",
doi = "10.1038/s41467-021-24225-2",
language = "English (US)",
volume = "12",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",
number = "1",
}