DOT-1.1 (DOT1L) deficiency in C. elegans leads to small RNA-dependent gene activation
Methylation of histone H3 at lysine 79 (H3K79) is conserved from yeast to humans and is accomplished by Dot1 (disruptor of telomeric silencing-1) methyltransferases. The C. elegans enzyme DOT-1.1 and its interacting partners are similar to the mammalian DOT1L (Dot1-like) complex. The C. elegans DOT-...
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| Format: | Article |
| Language: | English |
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Elsevier
2023-01-01
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| Series: | BBA Advances |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2667160323000091 |
| _version_ | 1797797966295072768 |
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| author | Thomas Liontis Karisma Verma Alla Grishok |
| author_facet | Thomas Liontis Karisma Verma Alla Grishok |
| author_sort | Thomas Liontis |
| collection | DOAJ |
| description | Methylation of histone H3 at lysine 79 (H3K79) is conserved from yeast to humans and is accomplished by Dot1 (disruptor of telomeric silencing-1) methyltransferases. The C. elegans enzyme DOT-1.1 and its interacting partners are similar to the mammalian DOT1L (Dot1-like) complex. The C. elegans DOT-1.1 complex has been functionally connected to RNA interference. Specifically, we have previously shown that embryonic and larval lethality of dot-1.1 mutant worms deficient in H3K79 methylation was suppressed by mutations in the RNAi pathway genes responsible for generation (rde-4) and function (rde-1) of primary small interfering RNAs (siRNAs). This suggests that dot-1.1 mutant lethality is dependent on the enhanced production of some siRNAs. We have also found that this lethality is suppressed by a loss-of-function of CED-3, a conserved apoptotic protease. Here, we describe a comparison of gene expression and primary siRNA production changes between control and dot-1.1 deletion mutant embryos. We found that elevated antisense siRNA production occurred more often at upregulated than downregulated genes. Importantly, gene expression changes were dependent on RDE-4 in both instances. Moreover, the upregulated group, which is potentially activated by ectopic siRNAs, was enriched in protease-coding genes. Our findings are consistent with a model where in the absence of H3K79 methylation there is a small RNA-dependent activation of protease genes, which leads to embryonic and larval lethality. DOT1 enzymes’ conservation suggests that the interplay between H3K79 methylation and small RNA pathways may exist in higher organisms. |
| first_indexed | 2024-03-13T03:56:20Z |
| format | Article |
| id | doaj.art-cfc86ec5313c4a9b85d04dbc8f50672a |
| institution | Directory Open Access Journal |
| issn | 2667-1603 |
| language | English |
| last_indexed | 2024-03-13T03:56:20Z |
| publishDate | 2023-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | BBA Advances |
| spelling | doaj.art-cfc86ec5313c4a9b85d04dbc8f50672a2023-06-22T05:05:53ZengElsevierBBA Advances2667-16032023-01-013100080DOT-1.1 (DOT1L) deficiency in C. elegans leads to small RNA-dependent gene activationThomas Liontis0Karisma Verma1Alla Grishok2Department of Biochemistry, Chobanian & Avedisian School of Medicine, Boston University, 72 East Concord Street, Boston, MA 02118, USA; Graduate Program in Genetics and Genomics, Chobanian & Avedisian School of Medicine, Boston University, Boston, MA 02118, USADepartment of Biochemistry, Chobanian & Avedisian School of Medicine, Boston University, 72 East Concord Street, Boston, MA 02118, USA; Program in Biochemistry and Molecular Biology, Boston University, 5 Cummington Mall, Boston, MA 02115, USADepartment of Biochemistry, Chobanian & Avedisian School of Medicine, Boston University, 72 East Concord Street, Boston, MA 02118, USA; Genome Science Institute, Boston University, Boston, MA 02118, USA; Corresponding author.Methylation of histone H3 at lysine 79 (H3K79) is conserved from yeast to humans and is accomplished by Dot1 (disruptor of telomeric silencing-1) methyltransferases. The C. elegans enzyme DOT-1.1 and its interacting partners are similar to the mammalian DOT1L (Dot1-like) complex. The C. elegans DOT-1.1 complex has been functionally connected to RNA interference. Specifically, we have previously shown that embryonic and larval lethality of dot-1.1 mutant worms deficient in H3K79 methylation was suppressed by mutations in the RNAi pathway genes responsible for generation (rde-4) and function (rde-1) of primary small interfering RNAs (siRNAs). This suggests that dot-1.1 mutant lethality is dependent on the enhanced production of some siRNAs. We have also found that this lethality is suppressed by a loss-of-function of CED-3, a conserved apoptotic protease. Here, we describe a comparison of gene expression and primary siRNA production changes between control and dot-1.1 deletion mutant embryos. We found that elevated antisense siRNA production occurred more often at upregulated than downregulated genes. Importantly, gene expression changes were dependent on RDE-4 in both instances. Moreover, the upregulated group, which is potentially activated by ectopic siRNAs, was enriched in protease-coding genes. Our findings are consistent with a model where in the absence of H3K79 methylation there is a small RNA-dependent activation of protease genes, which leads to embryonic and larval lethality. DOT1 enzymes’ conservation suggests that the interplay between H3K79 methylation and small RNA pathways may exist in higher organisms.http://www.sciencedirect.com/science/article/pii/S2667160323000091H3K79 methylationDOT1L, C. elegansRNAiSmall RNACED-3 |
| spellingShingle | Thomas Liontis Karisma Verma Alla Grishok DOT-1.1 (DOT1L) deficiency in C. elegans leads to small RNA-dependent gene activation BBA Advances H3K79 methylation DOT1L, C. elegans RNAi Small RNA CED-3 |
| title | DOT-1.1 (DOT1L) deficiency in C. elegans leads to small RNA-dependent gene activation |
| title_full | DOT-1.1 (DOT1L) deficiency in C. elegans leads to small RNA-dependent gene activation |
| title_fullStr | DOT-1.1 (DOT1L) deficiency in C. elegans leads to small RNA-dependent gene activation |
| title_full_unstemmed | DOT-1.1 (DOT1L) deficiency in C. elegans leads to small RNA-dependent gene activation |
| title_short | DOT-1.1 (DOT1L) deficiency in C. elegans leads to small RNA-dependent gene activation |
| title_sort | dot 1 1 dot1l deficiency in c elegans leads to small rna dependent gene activation |
| topic | H3K79 methylation DOT1L, C. elegans RNAi Small RNA CED-3 |
| url | http://www.sciencedirect.com/science/article/pii/S2667160323000091 |
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