Argonaute 4 as an Effector Protein in RNA-Directed DNA Methylation in Human Cells
Open accessAbstract
DNA methylation of specific genome locations contributes to the distinct functions of multicellular organisms. DNA methylation can be governed by RNA-dependent DNA methylation (RdDM). RdDM is carried out by endogenous small-RNA-guided epigenomic editing complexes that add a methyl group to a precise DNA location. In plants, the Argonaute 4 (AGO4) protein is one of the main catalytic components involved in RdDM. Although siRNA or shRNA has been shown to be able to guide DNA methylation in human cells, AGO protein-regulated RdDM in humans has not yet been evaluated. This study aimed to identify a key regulatory AGO protein involved in human RdDM by bioinformatics and to explore its function in RdDM by a combination of AGO4 knockdown, Alu siRNA transfection, AGO4-expressing plasmid transfection, chromatin immunoprecipitation, cell-penetrating peptide-tagged AGO4 (CPP-AGO4) combined Alu sgRNA transfection, and methylation analyses. We found that first, human AGO4 showed stronger genome-wide association with DNA methylation than AGO1-AGO3. Second, endogenous AGO4 depletion demethylated DNA of known AGO4 bound loci. Finally, exogenous AGO4 de novo methylated the bound DNA sequences. Therefore, we discovered that AGO4 plays a role in human RdDM.
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AGO4 plays a critical role in the RNA-directed DNA methylation complex.
“AGO4 (FC = −1.63, p = 0.04) plays a critical role in the RNA-directed DNA methylation complex [19], supporting altered DNA methylation patterns 24 h post-injury.”
From Early onset senescence and cognitive impairment in a murine model of repeated mTBI (2021) · cites this paper as [19]
AGO4 is a member of the Argonaute family that plays a role in DNA methylation and miRNA maintenance.
“AGO4 (FC = 1.33, p = 0.04) is a member of the Argonaute family which plays a role in DNA methylation and miRNA maintenance [19].”
From Early onset senescence and cognitive impairment in a murine model of repeated mTBI (2021) · cites this paper as [19]
CLEC7A is a disease-associated microglia gene that increases after TBI in mice, in a mouse model of Alzheimer's disease, and in aged microglia associated with neurodegenerative disease.
“CLEC7A (FC = 2.02, p = 0.02) is a disease-associated microglia gene which has been shown to increase after TBI in mice [19], in a mouse model of AD [38, 56], and in aged microglia associated with neurodegenerative disease [135].”
From Early onset senescence and cognitive impairment in a murine model of repeated mTBI (2021) · cites this paper as [19]
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References 61 · Cited by 43
- Authors
- Chalertpet, K., Pin-on, P., Aporntewan, C., Patchsung, M., Ingrungruanglert, P., Israsena, N., & Mutirangura, A.
- Affiliations
- Chulalongkorn University (TH)
- Corresponding author
- Mutirangura, Apiwat
- ORCID
- Venue
- Frontiers in Genetics
- Publisher
- Frontiers Media SA
- Published
- 2019-07-04
- Volume
- 10
- Pages
- 645-645
- ISSN
- 1664-8021 (ISSN-L)
- PMC
- PMC6620710
- OpenAlex
- W2950785043
- Cited by
- 43
- References
- 61
- Citations by year
- 2026: 3 · 2025: 9 · 2024: 9 · 2023: 4 · 2022: 11 · 2021: 6 · 2019: 1
- FWCI
- 1.49
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Frontiers in Genetics (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Greater South Information System
- Funders
- Thailand Research Fund (DPG5980005, RSA5980060, The Royal Golden Jubilee Ph.D. Program [PHD/0131/2554 to M.P. (student) and Professor A.M. (advisor)])
- National Science and Technology Development Agency (2019 Research Chair Grant)
- Chulalongkorn University (100th Year Birthday Anniversary Doctoral Degree Scholarship, The Chulalongkorn Academic Advancement in Its 2nd Century project)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › CRISPR and Genetic Engineering
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA regulation and disease
- Keywords
- RNA-directed DNA methylation, DNA methylation, small RNA, Alu elements, siRNA, CRISPR/Cas9, de novo methylation, epigenome editing, human cells
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