Oxygen gradients can determine epigenetic asymmetry and cellular differentiation via differential regulation of Tet activity in embryonic stem cells
Abstract Graded levels of molecular oxygen (O2) exist within developing mammalian embryos and can differentially regulate cellular specification pathways. During differentiation, cells acquire distinct epigenetic landscapes, which determine their function, however the mechanisms which regulate this...
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| Published in | Nucleic acids research Vol. 46; no. 3; pp. 1210 - 1226 |
|---|---|
| Main Authors | , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
England
Oxford University Press
16.02.2018
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| Subjects | |
| Online Access | Get full text |
| ISSN | 0305-1048 1362-4962 1362-4962 |
| DOI | 10.1093/nar/gkx1197 |
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| Abstract | Abstract
Graded levels of molecular oxygen (O2) exist within developing mammalian embryos and can differentially regulate cellular specification pathways. During differentiation, cells acquire distinct epigenetic landscapes, which determine their function, however the mechanisms which regulate this are poorly understood. The demethylation of 5-methylcytosine (5mC) is achieved via successive oxidation reactions catalysed by the Ten-Eleven-Translocation (Tet) enzymes, yielding the 5-hydroxymethylcytosine (5hmC) intermediate. These require O2 as a co-factor, and hence may link epigenetic processes directly to O2 gradients during development. We demonstrate that the activities of Tet enzymes display distinct patterns of [O2]-dependency, and that Tet1 activity, specifically, is subject to differential regulation within a range of O2 which is physiologically relevant in embryogenesis. Further, differentiating embryonic stem cells displayed a transient burst of 5hmC, which was both dependent upon Tet1 and inhibited by low (1%) [O2]. A GC-rich promoter region within the Tet3 locus was identified as a significant target of this 5mC-hydroxylation. Further, this region was shown to associate with Tet1, and display the histone epigenetic marks, H3K4me3 and H3K27me3, which are characteristic of a bivalent, developmentally 'poised' promoter. We conclude that Tet1 activity, determined by [O2] may play a critical role in regulating cellular differentiation and fate in embryogenesis. |
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| AbstractList | Graded levels of molecular oxygen (O2) exist within developing mammalian embryos and can differentially regulate cellular specification pathways. During differentiation, cells acquire distinct epigenetic landscapes, which determine their function, however the mechanisms which regulate this are poorly understood. The demethylation of 5-methylcytosine (5mC) is achieved via successive oxidation reactions catalysed by the Ten-Eleven-Translocation (Tet) enzymes, yielding the 5-hydroxymethylcytosine (5hmC) intermediate. These require O2 as a co-factor, and hence may link epigenetic processes directly to O2 gradients during development. We demonstrate that the activities of Tet enzymes display distinct patterns of [O2]-dependency, and that Tet1 activity, specifically, is subject to differential regulation within a range of O2 which is physiologically relevant in embryogenesis. Further, differentiating embryonic stem cells displayed a transient burst of 5hmC, which was both dependent upon Tet1 and inhibited by low (1%) [O2]. A GC-rich promoter region within the Tet3 locus was identified as a significant target of this 5mC-hydroxylation. Further, this region was shown to associate with Tet1, and display the histone epigenetic marks, H3K4me3 and H3K27me3, which are characteristic of a bivalent, developmentally 'poised' promoter. We conclude that Tet1 activity, determined by [O2] may play a critical role in regulating cellular differentiation and fate in embryogenesis.Graded levels of molecular oxygen (O2) exist within developing mammalian embryos and can differentially regulate cellular specification pathways. During differentiation, cells acquire distinct epigenetic landscapes, which determine their function, however the mechanisms which regulate this are poorly understood. The demethylation of 5-methylcytosine (5mC) is achieved via successive oxidation reactions catalysed by the Ten-Eleven-Translocation (Tet) enzymes, yielding the 5-hydroxymethylcytosine (5hmC) intermediate. These require O2 as a co-factor, and hence may link epigenetic processes directly to O2 gradients during development. We demonstrate that the activities of Tet enzymes display distinct patterns of [O2]-dependency, and that Tet1 activity, specifically, is subject to differential regulation within a range of O2 which is physiologically relevant in embryogenesis. Further, differentiating embryonic stem cells displayed a transient burst of 5hmC, which was both dependent upon Tet1 and inhibited by low (1%) [O2]. A GC-rich promoter region within the Tet3 locus was identified as a significant target of this 5mC-hydroxylation. Further, this region was shown to associate with Tet1, and display the histone epigenetic marks, H3K4me3 and H3K27me3, which are characteristic of a bivalent, developmentally 'poised' promoter. We conclude that Tet1 activity, determined by [O2] may play a critical role in regulating cellular differentiation and fate in embryogenesis. Abstract Graded levels of molecular oxygen (O2) exist within developing mammalian embryos and can differentially regulate cellular specification pathways. During differentiation, cells acquire distinct epigenetic landscapes, which determine their function, however the mechanisms which regulate this are poorly understood. The demethylation of 5-methylcytosine (5mC) is achieved via successive oxidation reactions catalysed by the Ten-Eleven-Translocation (Tet) enzymes, yielding the 5-hydroxymethylcytosine (5hmC) intermediate. These require O2 as a co-factor, and hence may link epigenetic processes directly to O2 gradients during development. We demonstrate that the activities of Tet enzymes display distinct patterns of [O2]-dependency, and that Tet1 activity, specifically, is subject to differential regulation within a range of O2 which is physiologically relevant in embryogenesis. Further, differentiating embryonic stem cells displayed a transient burst of 5hmC, which was both dependent upon Tet1 and inhibited by low (1%) [O2]. A GC-rich promoter region within the Tet3 locus was identified as a significant target of this 5mC-hydroxylation. Further, this region was shown to associate with Tet1, and display the histone epigenetic marks, H3K4me3 and H3K27me3, which are characteristic of a bivalent, developmentally 'poised' promoter. We conclude that Tet1 activity, determined by [O2] may play a critical role in regulating cellular differentiation and fate in embryogenesis. Graded levels of molecular oxygen (O2) exist within developing mammalian embryos and can differentially regulate cellular specification pathways. During differentiation, cells acquire distinct epigenetic landscapes, which determine their function, however the mechanisms which regulate this are poorly understood. The demethylation of 5-methylcytosine (5mC) is achieved via successive oxidation reactions catalysed by the Ten-Eleven-Translocation (Tet) enzymes, yielding the 5-hydroxymethylcytosine (5hmC) intermediate. These require O2 as a co-factor, and hence may link epigenetic processes directly to O2 gradients during development. We demonstrate that the activities of Tet enzymes display distinct patterns of [O2]-dependency, and that Tet1 activity, specifically, is subject to differential regulation within a range of O2 which is physiologically relevant in embryogenesis. Further, differentiating embryonic stem cells displayed a transient burst of 5hmC, which was both dependent upon Tet1 and inhibited by low (1%) [O2]. A GC-rich promoter region within the Tet3 locus was identified as a significant target of this 5mC-hydroxylation. Further, this region was shown to associate with Tet1, and display the histone epigenetic marks, H3K4me3 and H3K27me3, which are characteristic of a bivalent, developmentally 'poised' promoter. We conclude that Tet1 activity, determined by [O2] may play a critical role in regulating cellular differentiation and fate in embryogenesis. Graded levels of molecular oxygen (O 2 ) exist within developing mammalian embryos and can differentially regulate cellular specification pathways. During differentiation, cells acquire distinct epigenetic landscapes, which determine their function, however the mechanisms which regulate this are poorly understood. The demethylation of 5-methylcytosine (5mC) is achieved via successive oxidation reactions catalysed by the Ten-Eleven-Translocation (Tet) enzymes, yielding the 5-hydroxymethylcytosine (5hmC) intermediate. These require O 2 as a co-factor, and hence may link epigenetic processes directly to O 2 gradients during development. We demonstrate that the activities of Tet enzymes display distinct patterns of [O 2 ]-dependency, and that Tet1 activity, specifically, is subject to differential regulation within a range of O 2 which is physiologically relevant in embryogenesis. Further, differentiating embryonic stem cells displayed a transient burst of 5hmC, which was both dependent upon Tet1 and inhibited by low (1%) [O 2 ]. A GC-rich promoter region within the Tet3 locus was identified as a significant target of this 5mC-hydroxylation. Further, this region was shown to associate with Tet1, and display the histone epigenetic marks, H3K4me3 and H3K27me3, which are characteristic of a bivalent, developmentally ‘poised’ promoter. We conclude that Tet1 activity, determined by [O 2 ] may play a critical role in regulating cellular differentiation and fate in embryogenesis. |
| Author | Mistry, Rajesh K Arno, Matthew Mann, Giovanni E Caldwell, Anna Brewer, Alison C Chong, Mei Metcalf, Stephen Kropf, Valeria Leon Shah, Ajay M Beretta, Matteo Burr, Simon Balu, Sucharitha Hancock, Matthew |
| AuthorAffiliation | 3 King's Genomic Centre, King's College London, London SE1 9NH, UK 2 King's Centre of Excellence for Mass Spectrometry, King's College London, London SE1 9NH, UK 1 British Heart Foundation Centre of Research Excellence, Department of Cardiology, King's College London, London SE5 9NU, UK |
| AuthorAffiliation_xml | – name: 2 King's Centre of Excellence for Mass Spectrometry, King's College London, London SE1 9NH, UK – name: 3 King's Genomic Centre, King's College London, London SE1 9NH, UK – name: 1 British Heart Foundation Centre of Research Excellence, Department of Cardiology, King's College London, London SE5 9NU, UK |
| Author_xml | – sequence: 1 givenname: Simon surname: Burr fullname: Burr, Simon organization: British Heart Foundation Centre of Research Excellence, Department of Cardiology, King's College London, London SE5 9NU, UK – sequence: 2 givenname: Anna surname: Caldwell fullname: Caldwell, Anna organization: King's Centre of Excellence for Mass Spectrometry, King's College London, London SE1 9NH, UK – sequence: 3 givenname: Mei surname: Chong fullname: Chong, Mei organization: British Heart Foundation Centre of Research Excellence, Department of Cardiology, King's College London, London SE5 9NU, UK – sequence: 4 givenname: Matteo surname: Beretta fullname: Beretta, Matteo organization: British Heart Foundation Centre of Research Excellence, Department of Cardiology, King's College London, London SE5 9NU, UK – sequence: 5 givenname: Stephen surname: Metcalf fullname: Metcalf, Stephen organization: British Heart Foundation Centre of Research Excellence, Department of Cardiology, King's College London, London SE5 9NU, UK – sequence: 6 givenname: Matthew surname: Hancock fullname: Hancock, Matthew organization: British Heart Foundation Centre of Research Excellence, Department of Cardiology, King's College London, London SE5 9NU, UK – sequence: 7 givenname: Matthew surname: Arno fullname: Arno, Matthew organization: King's Genomic Centre, King's College London, London SE1 9NH, UK – sequence: 8 givenname: Sucharitha surname: Balu fullname: Balu, Sucharitha organization: King's Genomic Centre, King's College London, London SE1 9NH, UK – sequence: 9 givenname: Valeria Leon surname: Kropf fullname: Kropf, Valeria Leon organization: British Heart Foundation Centre of Research Excellence, Department of Cardiology, King's College London, London SE5 9NU, UK – sequence: 10 givenname: Rajesh K surname: Mistry fullname: Mistry, Rajesh K organization: British Heart Foundation Centre of Research Excellence, Department of Cardiology, King's College London, London SE5 9NU, UK – sequence: 11 givenname: Ajay M surname: Shah fullname: Shah, Ajay M organization: British Heart Foundation Centre of Research Excellence, Department of Cardiology, King's College London, London SE5 9NU, UK – sequence: 12 givenname: Giovanni E surname: Mann fullname: Mann, Giovanni E organization: British Heart Foundation Centre of Research Excellence, Department of Cardiology, King's College London, London SE5 9NU, UK – sequence: 13 givenname: Alison C surname: Brewer fullname: Brewer, Alison C email: alison.brewer@kcl.ac.uk organization: British Heart Foundation Centre of Research Excellence, Department of Cardiology, King's College London, London SE5 9NU, UK |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/29186571$$D View this record in MEDLINE/PubMed |
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| Copyright | The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research. 2017 |
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| Notes | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Present address: Alison Brewer, British Heart Foundation Centre of Research Excellence, Department of Cardiology, The James Black Centre, 125 Coldharbour Lane, London SE5 9NU, UK. |
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| Snippet | Abstract
Graded levels of molecular oxygen (O2) exist within developing mammalian embryos and can differentially regulate cellular specification pathways.... Graded levels of molecular oxygen (O2) exist within developing mammalian embryos and can differentially regulate cellular specification pathways. During... Graded levels of molecular oxygen (O 2 ) exist within developing mammalian embryos and can differentially regulate cellular specification pathways. During... |
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| SubjectTerms | 5-Methylcytosine - analogs & derivatives 5-Methylcytosine - metabolism Amino Acids, Dicarboxylic - pharmacology Animals Cell Differentiation - drug effects Cell Hypoxia Cell Line Demethylation Dioxygenases - genetics Dioxygenases - metabolism Embryoid Bodies - cytology Embryoid Bodies - metabolism Epigenesis, Genetic Gene Expression Regulation, Developmental Gene regulation, Chromatin and Epigenetics HEK293 Cells Histones - genetics Histones - metabolism Humans Hydroxylation Mice Mixed Function Oxygenases - genetics Mixed Function Oxygenases - metabolism Models, Biological Mouse Embryonic Stem Cells - cytology Mouse Embryonic Stem Cells - drug effects Mouse Embryonic Stem Cells - metabolism Oxygen - metabolism Oxygen - pharmacology Promoter Regions, Genetic Protein Isoforms - genetics Protein Isoforms - metabolism Proto-Oncogene Proteins - genetics Proto-Oncogene Proteins - metabolism |
| Title | Oxygen gradients can determine epigenetic asymmetry and cellular differentiation via differential regulation of Tet activity in embryonic stem cells |
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