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Ythdc1-p300-Klf5 complex-mediated Golgi dysfunction promotes aortic aneurysm

ABSTRACT: Klf5 and Golph3l-mediated regulation of Golgi morphology has been implicated in the development of apoptosis induced by diverse stress stimuli, and the loss of VSMCs caused by VSMCs apoptosis is a major factor leading to aortic wall thinning and aneurysm development. However, the molecular link between Klf5, Golph3l, and Golgi morphology alteration in the context of the aortic aneurysm is unclear. Here, we show that apoptosis-induced proliferation (AIP) in VSMCs occurs in AD and AAA tissues of humans and mice. The upregulation of Golph3l by Klf5 facilitates TNF-α and TNFSF12 secretion from AngII-stimulated VSMCs by inducing the compaction of the Golgi, which is essential for AIP and aneurysm development. Mechanistic studies reveal that AngII-induced elevation of global m6A RNA level, especially m6A-Gm40097, is responsible for Golph3l upregulation and AIP in VSMCs. Further, m6A-Gm40097 mediates Klf5 interaction with Ythdc1 and p300 to form a transcription complex on the Golph3l promoter, unveiling a novel lncRNA m6A modification-dependent regulatory mechanism of chromatin remodeling and transcription activation.

ORGANISM(S): Mus musculus

PROVIDER: GSE309196 | GEO | 2025/12/08

REPOSITORIES: GEO

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Project description:Background: Abdominal Aortic Aneurysm (AAA) is a catastrophic disease with little effective therapy, likely due to the limited understanding of the mechanisms underlying AAA development and progression. Activating transcription factor (ATF) 3 has been increasingly recognized as a key regulator of cardiovascular diseases. However, the role of ATF3 in AAA development and progression remains elusive. Methods: Genome-wide RNA sequencing analysis was performed on the aorta isolated from saline or Ang II-induced AAA mice, and ATF3 was identified as the potential key gene for AAA development. To examine the role of ATF3 in AAA development, vascular smooth muscle cell (VSMC)-specific ATF3 knockdown or overexpressed mice by recombinant adeno-associated virus serotype 9 (rAAV9) vectors carrying ATF3, or shRNA-ATF3 with SM22α promoter were used in AngII (angiotensin II) induced AAA mice. In human and murine VSMCs, gain or loss of function experiments were performed to investigate the role of ATF3 in VSMC proliferation and apoptosis. Results: In both AngII-induced AAA mice and AAA patients, the expression of ATF3 was reduced in aneurysm tissues but increased in aortic lesion tissues. The deficiency of ATF3 in VSMC promoted AAA formation in AngII-induced AAA mice. PDGFRB was identified as the target of ATF3, which mediated VSMC proliferation in response to TNF-alpha at the early stage of AAA. ATF3 suppressed the mitochondria-dependent apoptosis at the advanced stage by upregulating its direct target BCL2. Our ChIP results also demonstrated that the recruitment of NFκB1 and P300/BAF/H3K27ac complex to the ATF3 promoter induces ATF3 transcription via enhancer activation. NFKB1 inhibitor (Andrographolide) inhibits the expression of ATF3 by blocking the recruiters NFKB1 and ATF3-enhancer to the ATF3-promoter region, ultimately leading to AAA development. Conclusions: Our results demonstrate a previously unrecognized role of ATF3 in AAA development and progression, and ATF3 may serve as a novel therapeutic and prognostic marker for AAA.

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Ythdc1-p300-Klf5 complex-mediated Golgi dysfunction promotes aortic aneurysm

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