Kmt5a Controls Hepatic Metabolic Pathways by Facilitating RNA Pol II Release from Promoter-Proximal Regions
H4K20 monomethylation maintains genome integrity by regulating proper mitotic condensation, DNA damage response, and replication licensing. Here, we show that, in non-dividing hepatic cells, H4K20Me1 is specifically enriched in active gene bodies and dynamically regulated by the antagonistic action...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2017-07-01
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| Series: | Cell Reports |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124717309427 |
| _version_ | 1819030280517713920 |
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| author | Kostas C. Nikolaou Panagiotis Moulos Vangelis Harokopos George Chalepakis Iannis Talianidis |
| author_facet | Kostas C. Nikolaou Panagiotis Moulos Vangelis Harokopos George Chalepakis Iannis Talianidis |
| author_sort | Kostas C. Nikolaou |
| collection | DOAJ |
| description | H4K20 monomethylation maintains genome integrity by regulating proper mitotic condensation, DNA damage response, and replication licensing. Here, we show that, in non-dividing hepatic cells, H4K20Me1 is specifically enriched in active gene bodies and dynamically regulated by the antagonistic action of Kmt5a methylase and Kdm7b demethylase. In liver-specific Kmt5a-deficient mice, reduced levels of H4K20Me1 correlated with reduced RNA Pol II release from promoter-proximal regions. Genes regulating glucose and fatty acid metabolism were most sensitive to impairment of RNA Pol II release. Downregulation of glycolytic genes resulted in an energy starvation condition partially compensated by AMP-activated protein kinase (AMPK) activation and increased mitochondrial activity. This metabolic reprogramming generated a highly sensitized state that, upon different metabolic stress conditions, quickly aggravated into a senescent phenotype due to ROS overproduction-mediated oxidative DNA damage. The results illustrate how defects in the general process of RNA Pol II transition into a productive elongation phase can trigger specific metabolic changes and genome instability. |
| first_indexed | 2024-12-21T06:27:39Z |
| format | Article |
| id | doaj.art-2b0629ecbcb9486d83f91d4c90636761 |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-12-21T06:27:39Z |
| publishDate | 2017-07-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-2b0629ecbcb9486d83f91d4c906367612022-12-21T19:13:05ZengElsevierCell Reports2211-12472017-07-0120490992210.1016/j.celrep.2017.07.003Kmt5a Controls Hepatic Metabolic Pathways by Facilitating RNA Pol II Release from Promoter-Proximal RegionsKostas C. Nikolaou0Panagiotis Moulos1Vangelis Harokopos2George Chalepakis3Iannis Talianidis4Biomedical Sciences Research Center Alexander Fleming, 16672 Vari, GreeceBiomedical Sciences Research Center Alexander Fleming, 16672 Vari, GreeceBiomedical Sciences Research Center Alexander Fleming, 16672 Vari, GreeceDepartment of Biology, University of Crete, 71110 Herakleion, Crete, GreeceBiomedical Sciences Research Center Alexander Fleming, 16672 Vari, GreeceH4K20 monomethylation maintains genome integrity by regulating proper mitotic condensation, DNA damage response, and replication licensing. Here, we show that, in non-dividing hepatic cells, H4K20Me1 is specifically enriched in active gene bodies and dynamically regulated by the antagonistic action of Kmt5a methylase and Kdm7b demethylase. In liver-specific Kmt5a-deficient mice, reduced levels of H4K20Me1 correlated with reduced RNA Pol II release from promoter-proximal regions. Genes regulating glucose and fatty acid metabolism were most sensitive to impairment of RNA Pol II release. Downregulation of glycolytic genes resulted in an energy starvation condition partially compensated by AMP-activated protein kinase (AMPK) activation and increased mitochondrial activity. This metabolic reprogramming generated a highly sensitized state that, upon different metabolic stress conditions, quickly aggravated into a senescent phenotype due to ROS overproduction-mediated oxidative DNA damage. The results illustrate how defects in the general process of RNA Pol II transition into a productive elongation phase can trigger specific metabolic changes and genome instability.http://www.sciencedirect.com/science/article/pii/S2211124717309427histone methylationtranscriptionmetabolismgenome stabilityliver |
| spellingShingle | Kostas C. Nikolaou Panagiotis Moulos Vangelis Harokopos George Chalepakis Iannis Talianidis Kmt5a Controls Hepatic Metabolic Pathways by Facilitating RNA Pol II Release from Promoter-Proximal Regions Cell Reports histone methylation transcription metabolism genome stability liver |
| title | Kmt5a Controls Hepatic Metabolic Pathways by Facilitating RNA Pol II Release from Promoter-Proximal Regions |
| title_full | Kmt5a Controls Hepatic Metabolic Pathways by Facilitating RNA Pol II Release from Promoter-Proximal Regions |
| title_fullStr | Kmt5a Controls Hepatic Metabolic Pathways by Facilitating RNA Pol II Release from Promoter-Proximal Regions |
| title_full_unstemmed | Kmt5a Controls Hepatic Metabolic Pathways by Facilitating RNA Pol II Release from Promoter-Proximal Regions |
| title_short | Kmt5a Controls Hepatic Metabolic Pathways by Facilitating RNA Pol II Release from Promoter-Proximal Regions |
| title_sort | kmt5a controls hepatic metabolic pathways by facilitating rna pol ii release from promoter proximal regions |
| topic | histone methylation transcription metabolism genome stability liver |
| url | http://www.sciencedirect.com/science/article/pii/S2211124717309427 |
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