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RPB1 ChIP-Seq of NSC from Wild Type (WT) and Armc5 knockout mice

ABSTRACT: ARMC5 is a protein containing an armadillo domain (ARM) and a BTB domain. Its gene knockout caused many phenotypes, including dwarfism, compromise T-cell immunity, and adrenal gland hypertrophy. ARMC5 mutation in humans is associated with bilateral macronodular adrenal gland hypertrophy. We found that AMC5 KO mice suffered from an increased incidence of neural tube defects (NTDs). We revealed that ARMC5 complexed with CUL3 and POLR2A and was part of a novel POLR2A-specific ubiquitin ligase (E3). This E3 was the dominant DNA damage-independent POLR2A-specific E3 in developing neural tubes and neural precursor cells under a physiological condition. ARMC5 gene knockout (KO) caused diminished POLR2A ubiquitination and compromised POLR2A degradation via proteasomes. Surprisingly, the absence of this E3 did not lead to generalized Pol II stalling and the subsequent generalized decrease of mRNA transcription but caused an enlarged Pol II pool size, which dysregulated 108 genes in NPCs, including some known to neural development. ARMC5 KO in the intestine downregulated FOHL1 expression, which was essential in folate absorption. Whole-exome sequencing of 511 myelomeningocele (MM) patients revealed nine highly deleterious mutations in the ARMC5 coding sequence. A significant deleterious mutation Arg429Cys found in MM patients drastically weakened the interaction between ARMC5 and POLR2A, supporting our hypothesis that such mutations in ARMC5 increased the NTD risks by compromising the POLR2A-specific E3 activity. Our results indicated that this novel ARMC5-CUL3-RBX1 E3 played a critical role in Pol II pool homeostasis, and ARMC5 mutation was a modifier of NTD risks in mice and humans.

ORGANISM(S): Mus musculus

PROVIDER: GSE169582 | GEO | 2023/12/01

REPOSITORIES: GEO

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RNA-Seq of neural stem cells from Wild Type (WT) and Armc5 knockout mice

Project description:ARMC5 is a protein containing an armadillo domain (ARM) and a BTB domain. Its gene knockout caused many phenotypes, including dwarfism, compromise T-cell immunity, and adrenal gland hypertrophy. ARMC5 mutation in humans is associated with bilateral macronodular adrenal gland hypertrophy. We found that AMC5 KO mice suffered from an increased incidence of neural tube defects (NTDs). We revealed that ARMC5 complexed with CUL3 and POLR2A and was part of a novel POLR2A-specific ubiquitin ligase (E3). This E3 was the dominant DNA damage-independent POLR2A-specific E3 in developing neural tubes and neural precursor cells under a physiological condition. ARMC5 gene knockout (KO) caused diminished POLR2A ubiquitination and compromised POLR2A degradation via proteasomes. Surprisingly, the absence of this E3 did not lead to generalized Pol II stalling and the subsequent generalized decrease of mRNA transcription but caused an enlarged Pol II pool size, which dysregulated 108 genes in NPCs, including some known to neural development. ARMC5 KO in the intestine downregulated FOHL1 expression, which was essential in folate absorption. Whole-exome sequencing of 511 myelomeningocele (MM) patients revealed nine highly deleterious mutations in the ARMC5 coding sequence. A significant deleterious mutation Arg429Cys found in MM patients drastically weakened the interaction between ARMC5 and POLR2A, supporting our hypothesis that such mutations in ARMC5 increased the NTD risks by compromising the POLR2A-specific E3 activity. Our results indicated that this novel ARMC5-CUL3-RBX1 E3 played a critical role in Pol II pool homeostasis, and ARMC5 mutation was a modifier of NTD risks in mice and humans.

2023-12-01 | GSE169350 | GEO

ARMC5 controls the degradation of most Pol II subunits, and ARMC5 mutation increases neural tube defect risks in mice and humans

Project description:ARMC5 is an armadillo domain (ARM)-containing protein. We found that Armc5 KO mice had an increased incidence of neural tube defects (NTDs). ARMC5 is the substrate recognition component of a ubiquitin ligase that targets POLR2A, the largest subunit of RNA polymerase II (Pol II). Surprisingly, the absence of ARMC5 caused the accumulation of not only POLR2A, but most of the other 11 Pol II subunits associated with POLR2A, indicating that the degradation of the whole Pol II complex is compromised. This did not lead to generalized Pol II stalling or a generalized decrease in mRNA transcription. In neural progenitor cells, ARMC5 KO only dysregulated 106 genes, some of which are known to be involved in neural tube development. FOLH1, critical for folate metabolism and vital in neural tube development, was downregulated in the KO intestine, suggesting that it is a downstream effector gene for NTD. To assess whether ARMC5 gene mutation was associated with human NTD, we conducted whole-exome sequencing of 511 patients with myelomeningocele, a severe form of NTD. Nine deleterious single nucleotide variants were discovered in the ARMC5 coding sequence. Four of them were validated in that they weakened the interaction between ARMC5 and POLR2A; consequently, POLR2A ubiquitination was decreased. This proves that our findings in mice are relevant to human NTD; it also supports the role of Pol II in mediating NTD pathogenesis. Our findings indicate that mutations in ARMC5 increase the risk of NTD and support the role of Pol II in NTD pathogenesis. Further investigation is needed to determine the cause-and-effect relationship between an enlarged Pol II pool and NTD and to validate the potential role of downregulated FOLH1 expression in NTD pathogenesis.

2023-12-06 | PXD047572 | Pride

ARMC5 controls the degradation of most Pol II subunits, and ARMC5 mutation increases neural tube defect risks in mice and humans

2023-12-06 | PXD047533 | Pride

RPB1 ChIP-Seq of adrenal glands tissue from Wild Type (WT) and Armc5 knockout mice

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2022-05-20 | GSE169578 | GEO

RNA-Seq of adrenal glands tissue from Wild Type (WT) and Armc5 knockout mice

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ARMC5 selectively degrades SCAP-free SREBF1 and is essential for fatty acid desaturation in adipocytes

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2024-12-19 | GSE262941 | GEO

Distinct pathways for removal of defective RNA polymerase II transcription complexes at a promoter-proximal pause checkpointm [RN21236 dTAG TTchem-seq]

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2024-11-07 | GSE253354 | GEO

Distinct pathways for removal of defective RNA polymerase II transcription complexes at a promoter-proximal pause checkpoint

Project description:The Integrator complex interacts with RNA polymerase II (RNAPII) at promoter-proximal pause sites but its function there remains uncertain. Here, we show that when Integrator function is compromised by loss of INTS6, RNAPII interacts increasingly with proteins that mediate its dissociation from DNA, including CUL3-ARMC5, which ubiquitylates Ser5-phosphorylated Rpb1 and targets it for degradation. ARMC5-dependent RNAPII ubiquitylation is activated by defects in factors required for correctly regulated promoter-proximal pausing, including Integrator, DSIF and mRNA capping enzyme. This ARMC5 checkpoint curtails an appreciable fraction of RNAPII transcription, with ARMC5 knockout cells producing uncapped, nascent RNA transcripts that fail to mature into stable mRNA. Concomitant loss of INTS6 and ARMC5 greatly stabilizes RNAPII at the pause and has severe consequences for cell growth and viability. Our data support a model in which CRL3ARMC5 functions alongside Integrator in a checkpoint mechanism that removes faulty RNAPII complexes at promoter-proximal pause sites to safeguard transcription integrity.

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Distinct pathways for removal of defective RNA polymerase II transcription complexes at a promoter-proximal pause checkpoint [RN21114 Ttchemn-Seq]

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Ubiquitylation of Pol II controls early stages of the transcription cycle [dxChIP-seq]

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