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.
Highlights
STAT1α is a key transcription factor driving pro-inflammatory responses in macrophages
While we observed all expected outcomes, we were surprised by the large cohort of sites exhibiting a dramatic increase in occupancy with the STAT1α DBD mutant (DBDmut) compared to Wt (Fig. 5b–d). When we examined these sites in greater detail, we observed an enrichment of motifs for STAT3, IRF, and STAT5, but not STAT1α (Fig. 5e), suggesting that STAT1α DBDmut is redirected to DNA sequences that are distinct from its typical consensus sites
Activation of STAT1α by IFNγ leads to the induction of a transcriptional program that is coordinated, in a large part, by posttranslational modifications of STAT1α
Summary
STAT1α is a key transcription factor driving pro-inflammatory responses in macrophages. 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. We conclude that PARP-1-mediated ADPRylation of STAT1α drives distinct enhancer activation mechanisms and is a critical regulator of inflammatory responses in macrophages. One of the major cytokines that activates macrophages is interferon gamma (IFNγ)[24] and the modulation of gene expression by IFNγ occurs primarily through the Signal Transducers and Activators of Transcription (STAT) family member, STAT1
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