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Adipogenic Transcriptional Regulation Mediated by PARP7 Through NAD+ Sensing Mechanism [CUT&RUN]

ABSTRACT: The process of differentiating from a preadipocyte into a mature, fat storing, adipocyte (adipogenesis) is a complex and tightly regulated process vital to human health. The molecular mechanisms regulating adipogenesis are incompletely understood, although key facets of the signaling and regulatory pathways have been defined. Here we have identified a mono(ADP-ribosyl)transferase (MART), PARP7, that plays a pivotal role in adipogenesis. ADP-ribosylation – the process whereby specific members of the poly(ADP-ribosyl)polymerase (PARP) family facilitate the covalent transfer of ADP-ribose moieties from NAD+ to substrate proteins – has been shown to control multiple components of the adipogenic regulatory machinery. Herein we have found that PARP7 is required for modulation of the adipogenic transcriptional program during adipogenesis, and that the loss of PARP7 results in a decrease of the adipogenic process. Contrary to previous studies, the ability to modulate the adipogenic transcriptional program is independent of PARP7 catalytic activity. However, the catalytic activity of PARP7 plays a vital role in regulating protein stability, in a time and space specific manner, which is required for modulation of the adipogenic transcriptional program. This study has found a novel pathway which utilizes NAD+ compartmentalization to stabilize PARP7 at a specific time during the adipogenic process allowing for the regulation of adipogenic genes, through modulation of the well-known adipogenic transcription factor C/EBPß, in a time sensitive manner. Therefore, acting as another check and balance to the adipogenic differentiation process.

ORGANISM(S): Mus musculus

PROVIDER: GSE282095 | GEO | 2025/12/24

REPOSITORIES: GEO

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Adipogenic Transcriptional Regulation Mediated by PARP7 Through NAD+ Sensing Mechanism [RNA-Seq]

Project description:The process of differentiating from a preadipocyte into a mature, fat storing, adipocyte (adipogenesis) is a complex and tightly regulated process vital to human health. The molecular mechanisms regulating adipogenesis are incompletely understood, although key facets of the signaling and regulatory pathways have been defined. Here we have identified a mono(ADP-ribosyl)transferase (MART), PARP7, that plays a pivotal role in adipogenesis. ADP-ribosylation – the process whereby specific members of the poly(ADP-ribosyl)polymerase (PARP) family facilitate the covalent transfer of ADP-ribose moieties from NAD+ to substrate proteins – has been shown to control multiple components of the adipogenic regulatory machinery. Herein we have found that PARP7 is required for modulation of the adipogenic transcriptional program during adipogenesis, and that the loss of PARP7 results in a decrease of the adipogenic process. Contrary to previous studies, the ability to modulate the adipogenic transcriptional program is independent of PARP7 catalytic activity. However, the catalytic activity of PARP7 plays a vital role in regulating protein stability, in a time and space specific manner, which is required for modulation of the adipogenic transcriptional program. This study has found a novel pathway which utilizes NAD+ compartmentalization to stabilize PARP7 at a specific time during the adipogenic process allowing for the regulation of adipogenic genes, through modulation of the well-known adipogenic transcription factor C/EBPß, in a time sensitive manner. Therefore, acting as another check and balance to the adipogenic differentiation process.

2025-12-24 | GSE282094 | GEO

Adipogenic Transcriptional Regulation Mediated by PARP7 Through NAD+ Sensing Mechanism [ATAC-seq]

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Adipogenic Transcriptional Regulation Mediated by PARP7 Through NAD+ Sensing Mechanism [ChIP-Seq]

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Genome-wide CRISPR screens and quantitative proteomics reveal remodelling of the aryl hydrocarbon receptor-controlled proteome through PARP7 activity

Project description:PARP7 is an enzyme that uses donor substrate NAD+ to attach a single ADP-ribose moiety onto proteins related to immunity, transcription, and cell growth and motility. Despite the importance of PARP7 in these processes, PARP7 signalling networks remain under-researched. Here, we used genome-wide CRISPR screens and multiplex quantitative proteomics in distinct lung cancer cell lines treated with a PARP7 inhibitor to better understand PARP7 molecular functions. We discover that manipulating the aryl hydrocarbon receptor (AHR) transcriptional activity mediates PARP7 inhibitor sensitivity and triggers robust changes to the AHR-controlled proteome (AHR-ome). One of the striking features of such AHR-ome remodelling was the downregulation of Filamins A and B concurrent with the induction of the corresponding E3 ubiquitin ligase ASB2. We also show that suppressor of cytokine signalling 3 (SOCS3) reciprocally crosstalks to AHR. Inhibition of PARP7 in SOCS3 knockout cells leads to reduced viability compared to wild type cells treated with a PARP7 inhibitor. Our results reveal new signalling interplay among PARP7, AHR and SOCS3, and establish a useful resource to study the role of PARP7 in the regulation of AHR signalling and innate immunity through its ADP-ribosyl transferase activity.

2025-05-11 | PXD062520 | Pride

Parp7 generates an ADP-ribosyl degron that controls negative feedback of androgen signaling

Project description:The androgen receptor (AR) transduces the effects of circulating and tumor-derived androgens to the nucleus through ligand-induced changes in protein conformation, localization, and chromatin engagement. Defining how these events are integrated with signal transduction is critical to understand how AR drives prostate cancer and unveil pathway features that are potentially amenable to therapeutic intervention. We describe a novel post-transcriptional mechanism that controls AR levels on chromatin and gene output based on highly selective, inducible degradation. We find that the mono-ADP-ribosyltransferase PARP7 generates an ADP-ribosyl degron in the DNA-binding domain of AR, which is recognized by the ADP-ribose reader domain in the ubiquitin E3 ligase DTX2 and degraded by the proteasome. Mathematical modeling of the pathway suggested that PARP7 ADP-ribosylates chromatin-bound AR, a prediction that was validated in cells using an AR DNA-binding mutant. Non-conventional ubiquitin conjugation to ADP-ribosyl-cysteine and degradation by the proteasome forms the basis of a negative feedback loop that regulates modules of AR target genes. Our data expand the repertoire of mono-ADP-ribosyltransferases to include gene regulation via highly selective protein degradation.

2025-06-11 | GSE272500 | GEO

PARP7 is a proteotoxic stress sensor which labels proteins for degradation

Project description:ADP-ribosylation is a post-translational modification that plays a critical role in cellular stress responses. We have observed that during proteotoxic stress, cellular ADP-ribosylation increases, with ADP-ribosylated proteins accumulating in cytoplasmic foci containing ubiquitin and p62. During prolonged stress, these ADP-ribosylated proteins are transported to aggresomes and subsequently degraded via autophagy. In the absence of ubiquitination, ADP-ribosylated proteins become more prevalent and less soluble, indicating that ubiquitination is indispensable for this process. Upon inhibition of PARP7, accumulation of mono(ADP-ribosyl)ated proteins in response to proteotoxic stress is impeded. PARP7 turnover is very high under normal conditions, however, the protein stabilises following proteotoxic stress and thereby forms an ideal proteotoxic stress sensor. Finally, our findings imply that contrary to the current paradigm, perhaps not all ADP-ribosylation occurs on specific sites to regulate specific protein characteristics. Instead, it may be rather promiscuous to enable efficient protein degradation to prevent irreversible damage caused by defective proteins.

2025-09-01 | PXD065525 | Pride

Effect of RBN-2397, paclitaxel and their combination on ovarian cancer cell biology.

Project description:PARP7 (TiPARP), a mono (ADP-ribosyl) transferase (MART) was found to target α-tubulin proteins in ovarian cancer cells, enhancing their growth and migration. RBN-2397 is a potent inhibitor that selectively acts on PARP7. Here, we show that RBN-2397 treatment leads to the stabilization of microtubules in ovarian cancer cells, namely α-tubulin, mimicking what was previously observed with PARP7 knockdown. When treated with RBN-2397, we observe a decrease in growth and migration of ovarian cancer cells and, interestingly, the effect is intensified upon adding the microtubule stabilizing chemotherapeutic agent, paclitaxel. Mutating the site of α-tubulin MARylation by PARP7 similarly results in α-tubulin stabilization and decreased cell migration in the presence of paclitaxel when the tubulin network is further stabilized. In sum, we demonstrate that PARP7 inhibition decreases α-tubulin MARylation resulting in its stabilization, and ultimately leading to decreased ovarian cancer cell proliferation and migration. Finally, we show that combining PARP7 inhibitor and paclitaxel results in a more robust inhibition of aggressive ovarian cancer phenotypes. Collectively, this study highlights the potential of targeting PARP7 in combination with established chemotherapeutic agents to enhance treatment efficacy for ovarian cancer.

2024-10-01 | GSE268985 | GEO

Parp7 generates an ADP-ribosyl degron that controls negative feedback of androgen signaling

Project description:Parp7 generates an ADP-ribosyl degron that controls negative feedback of androgen signaling

| PRJNA1136979 | ENA

Coordinated metabolic transitions and gene expression by NAD+ during adipogenesis.

Project description:Adipocytes are the main cell type in adipose tissue, a critical regulator of metabolism, highly specialized in storing energy as fat. Adipocytes differentiate from multipotent mesenchymal stromal cells through adipogenesis. Using RNA-seq we explored the effect of manipulating NAD+ bioavailability during adipogenic differentiation from human mesenchymal stem cells. Cells were harvested either undifferentiated (hMSC) or after days 8 and 16 of adipogenic induction. During adipogenesis, cells were treated with either NAD+ (5 mM), or FK866 (1 nM) or EX527 (50 μM).

2022-09-16 | GSE178615 | GEO

Substrate Identification Using a Chemical Genetics Approach Reveals a Role for PARP-7-Mediated MARylation in Controlling Microtubule Stability in Ovarian Cancer Cells

Project description:ADP-ribosylation (ADPRylation) is a regulatory posttranslational modification of proteins that results in the covalent attachment of ADP-ribose (ADPR) moieties on target proteins. PARP-7 (TiPARP) is a monoADPR transferase whose proteins substrates and biological activities are poorly understood. Here, we describe a chemical genetics approach that has allowed us to identify substrates of PARP-7 and explore their biological functions. We observed reduced levels of PARP7 mRNA in ovarian cancer patient samples versus normal tissue, but found nonetheless that PARP-7 is required for a number of cancer-related biological endpoints in ovarian cancer cells, including growth, migration, and invasion. Global gene expression and gene ontology analyses in ovarian cancer cells subjected to siRNA-mediated knockdown of PARP7 revealed an enrichment of genes encoding proteins with roles in cell-cell adhesion, cell cycle arrest, apoptosis, and gene regulation. To identify the ADPRylated substrates that underlie PARP-7-mediated ovarian cancer cell phenotypes, we developed an NAD+ analog-sensitive approach for PARP-7 comprising a PARP-7 NAD+ binding pocket mutant (S563G) paired with the NAD+ analog 8-Bu(3-yne)T-NAD+. When coupled with mass spectrometry, this approach allowed us to identify the PARP-7 ADP-ribosylated proteome in ovarian cancer cells, including components of the cell-cell adhesion and cytoskeleton organization machinery. Specifically, we found that PARP-7 monoADPRylates α-tubulin to promote microtubule instability, which may play a key role in the regulating ovarian cancer cell growth and motility. Collectively, our results point to an extensive PARP-7 ADP-ribosylated proteome with important roles in cancer-related cellular phenotypes.

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