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Effect of depletion of ZFC3H1, PABPN1 and CNOT4 on gene expression in human cells.

ABSTRACT: Codon usage bias of an organism has been reported to affect the level of gene expression by influencing this process at multiple steps. Here, we have identified a role of poly-A exosome targeting complex (PAXT), which is a substrate adaptor of nuclear RNA exosome, in regulating codon usage effect on gene expression. PAXT complex subunits, ZFC3H1 and PABPN1, regulate stability and subcellular localization of mRNA in a codon usage dependent manner. This suggests that codon usage dependent mRNA stability and nuclear export are important factors of codon usage effect on gene expression in human cells. Also, a subunit of CCR4-NOT complex, CNOT4, was found to play a significant role in this regulation by affecting the nuclear mRNA levels and their subcellular localization in codon usage dependent manner.

ORGANISM(S): Homo sapiens

PROVIDER: GSE261505 | GEO | 2025/10/17

REPOSITORIES: GEO

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Effect of depletion of CNOT4 on gene expression in human cells

Project description:Codon usage bias of an organism plays an important role in determining its gene expression levels. Here, we have identified that a subunit of CCR4-NOT complex, CNOT4, plays a significant role in mediating codon usage effect on gene expression in human cells by affecting mRNA levels in a codon usage dependent manner.

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Project description:CCR4-NOT regulates multiple steps in gene regulation, including transcription, mRNA decay, protein ubiquitylation and translation. Originally discovered in yeast, this complex is highly conserved across eukaryotes, although its composition and functions differ between mammals and yeast. For example, unlike yeast Not4, human CNOT4 (E3 Ubiquitin Ligase) does not form a stable complex with CCR4-NOT, and its functions are less clear compared to its yeast counterpart. To investigate the roles of CNOT1 (the central scaffold subunit) and CNOT4, we developed a rapid auxin-induced degron cell culture system that allows for the acute depletion of these proteins. We studied the effects of their absence on complex integrity, cell growth, and mRNA expression and turnover. Our transcriptome-wide analysis revealed that depleting CNOT1 altered the expression of thousands of transcripts, with the majority showing increased abundance and a general decrease in mRNA decay. Although CNOT4 does not associate with the complex through standard biochemical methods, BioID proximity labelling confirmed its association with the complex in cells. However, depleting CNOT4 did not affect the integrity of CCR4-NOT. In contrast to the effects observed with CNOT1 depletion, reducing CNOT4 levels led to only modest changes in RNA steady-state levels and unexpectedly accelerated global mRNA decay. Finally, we show that the changes in mRNA stability in CCR4-NOT depleted cells correlated with the codon optimality of the transcripts. Our data suggest that CNOT4 exerts opposite effects on mRNA metabolism compared to CNOT1, and that CNOT4 may have functions distinct from those of complex subunits that promote mRNA degradation.

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Dual agonistic and antagonistic roles of ZC3H18 provides for co-activation of distinct nuclear RNA decay pathways

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Dual agonistic and antagonistic roles of ZC3H18 provides for co-activation of distinct nuclear RNA decay pathways

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PAP-gamma associates with PAXT nuclear exosome to control the abundance of PROMPT ncRNAs

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