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NUDT21 Shapes Macrophage Transcriptomes through alternative polyadenylation in ARDS

ABSTRACT: Defining the molecular mechanisms governing macrophage-driven inflammation is essential for developing targeted interventions for ARDS. One such mechanism could be alternative polyadenylation (APA), a post-transcriptional regulatory process that plays a critical role in gene regulation. Most mammalian genes, including key proinflammatory mediators, contain multiple polyadenylation sites (PAS). APA regulates the addition of poly(A) tails at alternative PAS, generating transcripts with different 3' UTR lengths. One key regulator of APA is Nudix Hydrolase 21 (NUDT21), a critical cleavage factor Im (CFIm) component. However, whether NUDT21-mediated APA plays a role in inflammation during ARDS is not known. Thus, the goal of this study is to identify the APA genes regulated by NUDT21 in macrophages.

ORGANISM(S): Mus musculus

PROVIDER: GSE292996 | GEO | 2025/08/11

REPOSITORIES: GEO

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Interacting proteins of NUDT21 identified by IP-MS

Project description:Alternative polyadenylation modulates gene expresion via changing the length of 3'UTR. Among the complexes involving in APA, CFIm complex plays a central role in determining the usage of proximal PAS versus distal one. NUDT21, also named as CFIm25 and CPSF5, is the core component of CFIm complex. To date, except CPSF6 and CPSF7, there are few proteins reported to interact with NUDT21. In this project, the interactome of NUDT21 was identified by IP-MS.

2022-01-21 | PXD031134 |

NUDT21 regulates intron detention of the SAM synthetase MAT2A RNA

Project description:NUDT21 encodes the CFIm25 protein, a component of the CFIm complex that regulates alternative polyadenylation (APA). Our data suggest that the CFIm complex also induces splicing of a detained intron in the the S-adenosylmethionine (SAM) synthetase MAT2A to control intracellular levels of SAM. To genetically separate these functions, we used poly(A) Click-seq (PAC-seq) to determine the changes in poly(A) site selection in two cell lines. The parental cell line is the colorectal cell line HCT116 and a derivative line that has the detained intron of MAT2A deleted in both alleles of MAT2A (116-DDI). We found few differences in alternative polyadenylation after CFIm25 depletion were similar supporting teh conclusion that CFIm's role in APA is mechanistically distinct from its role in regulation of MATA splicing.

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NUDT21 lactylation reprograms alternative polyadenylation to promote cuproptosis resistance

Project description:Alternative polyadenylation (APA) serves as a critical mechanism for shaping transcriptome diversity and modulating cancer therapeutic resistance. While lactate is a well-established metabolic signal in cancer progression, its role in APA regulation remains unclear. Here, we demonstrate that L-lactate-induced lactylation of NUDT21 drives transcriptomic reprogramming through APA modulation. NUDT21 lactylation enhances its interaction with CPSF6, facilitating CFIm complex formation and inducing 3′ untranslated region (UTR) lengthening of FDX1. Extension of the FDX1 3′ UTR attenuates its protein output, thereby conferring resistance to cuproptosis in esophageal squamous cell carcinoma (ESCC). Furthermore, we identify AARS1 as the lactylation “writer” catalyzing NUDT21 K23 lactylation, and HDAC2 as its enzymatic “eraser”. Clinically, elevated LDHA and NUDT21 levels correlate with reduced FDX1 expression and worse prognosis in ESCC patients. Notably, combined targeting of the lactate-NUDT21-FDX1-cuproptosis axis with the clinical LDHA inhibitor stiripentol and the copper ionophore elesclomol synergistically suppressed tumor growth. Collectively, our work identifies lactylated NUDT21 as a critical factor linking cellular metabolism to APA and proposes a promising therapeutic strategy for ESCC treatment.

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NUDT21 Shapes Macrophage Transcriptomes through alternative polyadenylation in ARDS

Project description:NUDT21 Shapes Macrophage Transcriptomes through alternative polyadenylation in ARDS

| PRJNA1242320 | ENA

NUDT21 Negatively Regulates PSMB2 and CXXC5 by Alternative Polyadenylation and Contributes to Hepatocellular Carcinoma Suppression

Project description:HCC is the third leading cause of cancer-related deaths worldwide. However, the molecular mechanisms underlying the progression of HCC is still largely elusive. NUDT21 (CFIm25) is an important mediator of 3′ UTR APA and demonstrates a causal relationship between alternative polyadenylation and cancer cell proliferation. Although the function of NUDT21 has been explored in glioblastoma tumor, the functional significance of NUDT21 in solid tumors is not well understood. In this study, we observed that NUDT21 is suppressed in human HCC tissues, compared to adjacent noncancerous tissues. In addition we found that the HCC patients with suppressed NUDT21 are statistically associated with poor outcomes. These observations suggest NUDT21 possibly functions as tumor suppressor in hepatocellular carcinoma (HCC).

2018-01-25 | E-MTAB-6368 | biostudies-arrayexpress

CRISPR screen identifies NUDT21 as a regulator of intron detention of the SAM synthetase MAT2A RNA

Project description:The only S-adenosymethionine (SAM) synthetase expressed in most human cells, MAT2A, is regulated by intron detention. Using a GFP fusion reporter, we conducted a CRISPR screen to identify regulators of this alternative splicing event. The screen identified METTL16, a known regulator of this process, and NUDT21. NUDT21 encodes the CFIm25 protein a member of the CFIm complex involved in alternative polyadenylation. Validation and follow-up studies support the idea that CFIm25 and the larger CFIm complex plays an unanticipated role in splicing of the MAT2A detained intron.

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Project description:Macrophage hyperactivation is a hallmark of inflammatory diseases, yet the role of alternative polyadenylation (APA) in regulating innate immunity remains unclear. In this study, we demonstrate that Nudt21, a crucial RNA-binding component of the APA machinery, is significantly upregulated in various inflammatory settings. Utilizing myeloid-specific Nudt21-deficient mice, we reveal a protective effect of Nudt21 depletion against colitis and severe hyperinflammation, primarily through diminished production of proinflammatory cytokines. Notably, Nudt21 regulates the mRNA stability of key autophagy-related genes by mediating selective 3’UTR polyadenylation in activated macrophages. As a result, Nudt21-deficient macrophages display enhanced autophagic activity, which leads to reduced cytokine secretion.

2025-01-24 | GSE267291 | GEO

SRSF7 and SRSF3 affectSRSF7 and SRSF3 affect 3’UTR length in opposite directions by controlling proximal poly(A)-site usage and CFIm levels 3’UTR length in opposite directions by controlling proximal poly(A)-site usage and CFIm levels

Project description:Alternative polyadenylation (APA) refers to the regulated selection of polyadenylation sites (PASs) in transcripts, which affects the length of their 3’ untranslated regions (3’UTRs). APA regulates stage- and tissue-specific gene expression by affecting the stability, subcellular localization or translation rate of transcripts. We have recently shown that SRSF3 and SRSF7, two closely related SR proteins, link APA to mRNA export. However, the underlying mechanism for APA regulation by SRSF3 and SRSF7 remained unknown. Here, we combined iCLIP and 3’-end sequencing to find that both proteins bind upstream of proximal PAS (pPAS), but exert opposing effects on 3’UTR length. We show that SRSF7 enhances pPAS usage in a splicing-independent and concentration-dependent manner by recruiting the cleavage factor FIP1, thereby generating short 3’UTRs. SRSF7-specific domains that are absent in SRSF3 are necessary and sufficient for FIP1 recruitment. SRSF3 promotes long 3’UTRs by maintaining high levels of the cleavage factor Im (CFIm) via alternative splicing. Using iCLIP, we show that CFIm binds before and after the pPASs of SRSF3 targets, which masks them and inhibits polyadenylation. In the absence of SRSF3, CFIm levels are strongly reduced, which exposes the pPASs and leads to shorter 3’UTRs. Conversely, during cellular differentiation, 3’UTRs are massively extended, while the levels of SRSF7 and FIP1 strongly decline. Altogether, our data suggest that SRSF7 acts as a sequence-specific enhancer of pPASs, while SRSF3 inhibits pPAS usage by controlling CFIm levels. Our data shed light on a long-standing puzzle of how one factor (CFIm) can inhibit and enhance PAS usage.

2021-09-09 | PXD018090 | Pride

A jack of all trades and a master of some: remodeling of signaling pathways downstream of CFIm 3’ end processing factor

Project description:The mammalian cleavage factor I (CFIm) has been implicated in alternative polyadenylation (APA) in a broad range of contexts, from cancers to learning deficits and parasite infections. To uncover the molecular pathways that translate CFIm expression levels into these observed phenotypes, we carried out a multi-omics analysis of cell lines in which the CFIm25 (NUDT21) or CFIm68 (CPSF6) subunits were either repressed by siRNA-mediated knockdown or over-expressed from stably integrated constructs. We established that more than 600 genes exhibit CFIm-dependent APA, and they cluster in distinct functional classes related to protein metabolism. The activity of the ERK pathway traces the CFIm concentration, and explains some of the metabolic and proliferation changes induced by CFIm perturbations. Transcripts of miRNA pathway proteins are prominent targets of CFIm-dependent APA. This leads to increased miRNA biogenesis and repressive activity at the same time as 3’ UTRs become shorter upon CFIm depletion. Our study provides a first systematic assessment of the signalling pathways downstream of CFIm to improve our understanding of CFIm-dependent phenotypes.

2022-02-11 | PXD027034 | Pride

Nudt21 controls cell fate by connecting alternative polyadenylation to chromatin signaling

Project description:Cell fate transitions involve rapid changes of gene expression patterns and global chromatin remodeling, yet the underlying regulatory pathways remain incompletely understood. Here, we used transcription-factor induced reprogramming of somatic cells into pluripotent cells to screen for novel regulators of cell fate change. We identified the RNA processing factor Nudt21, a component of the pre-mRNA cleavage and polyadenylation complex, as a potent barrier to reprogramming. Importantly, suppression of Nudt21 not only enhanced the generation of induced pluripotent stem cells but also facilitated the conversion of fibroblasts into trophoblast stem cells and delayed the differentiation of myeloid precursor cells into macrophages, suggesting a broader role for Nudt21 in restricting cell fate change. Polyadenylation site sequencing (PAS-seq) revealed that Nudt21 directs differential polyadenylation of over 1,500 transcripts in cells acquiring pluripotency. While only a fraction of these transcripts changed expression at the protein level, this fraction was strongly enriched for chromatin regulators, including components of the PAF, polycomb, and trithorax complexes. Co-suppression analysis further suggests that these chromatin factors are largely responsible for Nudt21’s effect on reprogramming, providing a mechanistic basis for our observations. Collectively, our data uncover Nudt21 as a novel post-transcriptional regulator of mammalian cell fate and establish a direct, previously unappreciated link between alternative polyadenylation and chromatin signaling.

2018-01-08 | PXD008078 | Pride

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