Feedback regulation between ALKBH3-mediated glycolysis and histone lactylation promotes age-related macular degeneration
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ABSTRACT:
PROVIDER: PRJNA1146349 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR30184581_1.fastq.gz | Fastqsanger.gz | |||
| SRR30184581_2.fastq.gz | Fastqsanger.gz | |||
| SRR30184582_1.fastq.gz | Fastqsanger.gz | |||
| SRR30184582_2.fastq.gz | Fastqsanger.gz | |||
| SRR30184583_1.fastq.gz | Fastqsanger.gz |
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Project description:Age-related macular degeneration (AMD) is a leading cause of blindness among the elderly. Using clinical samples and knockout mice, we reported that the m1A eraser ALKBH3 reshaped retinal metabolism to promote AMD. In retinal pigment epithelium (RPE), the dm1ACRISPR system demonstrated that ALKBH3 demethylated the glycolytic enzyme HK2 to activate anaerobic glycolysis, producing excessive lactate. The lactate promoted histone lactylation at H3K18, which in turn bound to ALKBH3 to amplify its transcription, establishing a positive feedback loop. The ALKBH3 inhibitor HUHS015 disrupted this loop, effectively mitigating RPE degeneration. Furthermore, ALKBH3 directly targeted the pro-angiogenic factor VEGFA to modulate the metabolic cross-talk between RPE and choroidal capillaries, thus promoting choroidal neovascularization (CNV). HUHS015 inhibited CNV synergistically with the anti-VEGF drug Aflibercept. Our study provides critical insights into the molecular mechanisms and metabolic events facilitating the progression from RPE degeneration to CNV in AMD, laying the groundwork for new treatments of AMD.
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Project description:Longstanding evidence implicates glioma stem cells (GSCs) as the major driver for glioma propagation and recurrence. GSCs have a distinctive metabolic landscape characterized by elevated glycolysis. Lactate accumulation resulting from enhanced glycolytic activity can drive lysine lactylation to regulate protein functions, suggesting that elucidating the lactylation landscape in GSCs could provide insights into glioma biology. Herein, we demonstrated that global lactylation was significantly elevated in GSCs compared to differentiated glioma cells (DGCs). PTBP1, a central regulator of RNA processing, was hyperlactylated in GSCs, and SIRT1 induced PTBP1 delactylation. PTBP1-K436 lactylation supported glioma progression and GSC maintenance. Mechanistically, K436 lactylation inhibited PTBP1 proteasomal degradation by attenuating the interaction with TRIM21. Moreover, PTBP1 lactylation enhanced its RNA-binding capacity and facilitated PFKFB4 mRNA stabilization, which further increased glycolysis. Together, these findings uncovered a lactylation-mediated mechanism in GSCs driven by metabolic reprogramming that induces aberrant epigenetic modifications to further stimulate glycolysis, resulting in a vicious cycle to exacerbate tumorigenesis.
2024-11-05 | GSE262995 | GEO
Project description:Background: The oxidative DNA demethylase ALKBH3 targets single-stranded DNA (ssDNA) in order to perform DNA alkylation damage repair. ALKBH3 becomes up-regulated during tumorigenesis and is necessary for proliferation. However, the underlying molecular mechanism remains to be understood. Methods: To further elucidate the function of ALKBH3 in cancer, we performed ChIP-seq to investigate the genomic binding pattern of endogenous ALKBH3 in PC3 prostate cancer cells coupled with microarray experiments to examine the expression effects of ALKBH3 depletion. Results: We demonstrate that ALKBH3 binds to transcription associated locations, such as places of promoter-proximal paused RNA polymerase II and enhancers. Strikingly, ALKBH3 strongly binds to the transcription initiation sites of a small number of highly active gene promoters. These promoters are characterized by high levels of transcriptional regulators, including transcription factors, the Mediator complex, cohesin, histone modifiers and active histone marks. Gene expression analysis showed that ALKBH3 does not directly influence the transcription of its target genes, but its depletion induces an up-regulation of ALKBH3 non-bound inflammatory genes. Conclusions: The genomic binding pattern of ALKBH3 revealed a putative novel hyperactive promoter type. Further, we propose that ALKBH3 is an intrinsic DNA repair protein that suppresses transcription associated DNA damage at highly expressed genes and thereby plays a role to maintain genomic integrity in ALKBH3-overexpressing cancer cells. These results raise the possibility that ALKBH3 may be a potential target for inhibiting cancer progression. PC3 cells were infected with ALKBH3 shRNA or Control shRNA for 48 hours and selected with puromycine. Cells were collected after 48h or 96h past selection.
2015-06-05 | E-GEOD-57568 | biostudies-arrayexpress
Project description:Age-related macular degeneration has a strong epidemiological association with cardiovascular disease. One pathogenic hypothesis that applies to both diseases is the concept of an abnormal cellular response to injury resulting in a disease phenotype. It has been hypothesized that this phenotype is also present in dermal fibroblasts. This study tests this hypothesis by examination of the expression profiles of fibroblasts obtained from diseased patients and subjected to sublethal cell injury. Keywords: other
2004-09-02 | GSE1719 | GEO
Project description:Background: The oxidative DNA demethylase ALKBH3 targets single-stranded DNA (ssDNA) in order to perform DNA alkylation damage repair. ALKBH3 becomes up-regulated during tumorigenesis and is necessary for proliferation. However, the underlying molecular mechanism remains to be understood. Methods: To further elucidate the function of ALKBH3 in cancer, we performed ChIP-seq to investigate the genomic binding pattern of endogenous ALKBH3 in PC3 prostate cancer cells coupled with microarray experiments to examine the expression effects of ALKBH3 depletion. Results: We demonstrate that ALKBH3 binds to transcription associated locations, such as places of promoter-proximal paused RNA polymerase II and enhancers. Strikingly, ALKBH3 strongly binds to the transcription initiation sites of a small number of highly active gene promoters. These promoters are characterized by high levels of transcriptional regulators, including transcription factors, the Mediator complex, cohesin, histone modifiers and active histone marks. Gene expression analysis showed that ALKBH3 does not directly influence the transcription of its target genes, but its depletion induces an up-regulation of ALKBH3 non-bound inflammatory genes. Conclusions: The genomic binding pattern of ALKBH3 revealed a putative novel hyperactive promoter type. Further, we propose that ALKBH3 is an intrinsic DNA repair protein that suppresses transcription associated DNA damage at highly expressed genes and thereby plays a role to maintain genomic integrity in ALKBH3-overexpressing cancer cells. These results raise the possibility that ALKBH3 may be a potential target for inhibiting cancer progression.
2015-06-05 | GSE57568 | GEO
Project description:Embryonic stem cells (ESCs) favor glycolysis over oxidative phosphorylation for energy production, and glycolytic metabolism is critical for pluripotency establishment, maintenance and exit. However, how glycolysis regulates the self-renewal and differentiation of ESCs remains elusive. Here, we demonstrated that protein lactylation, regulated by intracellular lactate, contributes to the self-renewal of ESCs. Next, the lactylome profiles of ESCs with and without a lactate dehydrogenase (Ldh) inhibitor, which suppresses the conversion of pyruvate to lactate, were depicted. It was notable that many lactylated proteins are involved in the self-renewal and differentiation of ESCs. We further showed that Esrrb, an orphan nuclear receptor involved in pluripotency maintenance and extraembryonic endoderm stem cell (XEN) differentiation, is lactylated on K228 and K232. Lactylation of Esrrb enhances its activity in promoting ESC self-renewal in the absence of LIF and XEN differentiation of ESCs, through increasing its binding at target genes. Our studies reveal the importance of protein lactation in the self-renewal and XEN differentiation of ESCs, and the underlying mechanism for glycolytic metabolism regulating cell fate choice.
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Project description:This SuperSeries is composed of the following subset Series: GSE28002: Gene expression of the whole mouse eye GSE28032: Epigenetic Regulation of IL17RC in Age-related Macular Degeneration (MeDIP-chip) Refer to individual Series
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Project description:PTBP1 Lactylation Promotes Glioma Stem Cell Maintenance through PFKFB4-Driven Glycolysis
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Project description:In order to study the mechanism of histone lactylation, we used glycolysis inhibitors to reduce histone lactylation and applied RNA-seq and ChIP-seq to identify its target genes in ocular melanoma.
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Project description:To study the mechanism of ALKBH3 in ocular melanoma, we performed RNA-seq of wide type cells and ALKBH3-deficient cells.
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