Human monocyte-to-macrophage differentiation involves highly localized gain and loss of DNA methylation at transcription factor binding sites
Abstract Background Macrophages and their precursors monocytes play a key role in inflammation and chronic inflammatory disorders. Monocyte-to-macrophage differentiation and activation programs are accompanied by significant epigenetic remodeling where DNA methylation associates with cell identity....
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| Format: | Article |
| Language: | English |
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BMC
2019-06-01
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| Series: | Epigenetics & Chromatin |
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| Online Access: | http://link.springer.com/article/10.1186/s13072-019-0279-4 |
| _version_ | 1830491239084982272 |
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| author | Koen F. Dekkers Annette E. Neele J. Wouter Jukema Bastiaan T. Heijmans Menno P. J. de Winther |
| author_facet | Koen F. Dekkers Annette E. Neele J. Wouter Jukema Bastiaan T. Heijmans Menno P. J. de Winther |
| author_sort | Koen F. Dekkers |
| collection | DOAJ |
| description | Abstract Background Macrophages and their precursors monocytes play a key role in inflammation and chronic inflammatory disorders. Monocyte-to-macrophage differentiation and activation programs are accompanied by significant epigenetic remodeling where DNA methylation associates with cell identity. Here we show that DNA methylation changes characteristic for monocyte-to-macrophage differentiation occur at transcription factor binding sites, and, in contrast to what was previously described, are generally highly localized and encompass both losses and gains of DNA methylation. Results We compared genome-wide DNA methylation across 440,292 CpG sites between human monocytes, naïve macrophages and macrophages further activated toward a pro-inflammatory state (using LPS/IFNγ), an anti-inflammatory state (IL-4) or foam cells (oxLDL and acLDL). Moreover, we integrated these data with public whole-genome sequencing data on monocytes and macrophages to demarcate differentially methylated regions. Our analysis showed that differential DNA methylation was most pronounced during monocyte-to-macrophage differentiation, was typically restricted to single CpGs or very short regions, and co-localized with lineage-specific enhancers irrespective of whether it concerns gain or loss of methylation. Furthermore, differentially methylated CpGs were located at sites characterized by increased binding of transcription factors known to be involved in monocyte-to-macrophage differentiation including C/EBP and ETS for gain and AP-1 for loss of methylation. Conclusion Our study highlights the involvement of subtle, yet highly localized remodeling of DNA methylation at regulatory regions in cell differentiation. |
| first_indexed | 2024-12-21T20:06:32Z |
| format | Article |
| id | doaj.art-5ccb0cea0ba542819cf607b568f93f16 |
| institution | Directory Open Access Journal |
| issn | 1756-8935 |
| language | English |
| last_indexed | 2024-12-21T20:06:32Z |
| publishDate | 2019-06-01 |
| publisher | BMC |
| record_format | Article |
| series | Epigenetics & Chromatin |
| spelling | doaj.art-5ccb0cea0ba542819cf607b568f93f162022-12-21T18:51:50ZengBMCEpigenetics & Chromatin1756-89352019-06-0112111310.1186/s13072-019-0279-4Human monocyte-to-macrophage differentiation involves highly localized gain and loss of DNA methylation at transcription factor binding sitesKoen F. Dekkers0Annette E. Neele1J. Wouter Jukema2Bastiaan T. Heijmans3Menno P. J. de Winther4Molecular Epidemiology, Department of Biomedical Data Sciences, Leiden University Medical CenterDepartment of Medical Biochemistry, Amsterdam Cardiovascular Sciences, Meibergdreef 9, Amsterdam UMC, University of AmsterdamDepartment of Cardiology, Leiden University Medical CenterMolecular Epidemiology, Department of Biomedical Data Sciences, Leiden University Medical CenterDepartment of Medical Biochemistry, Amsterdam Cardiovascular Sciences, Meibergdreef 9, Amsterdam UMC, University of AmsterdamAbstract Background Macrophages and their precursors monocytes play a key role in inflammation and chronic inflammatory disorders. Monocyte-to-macrophage differentiation and activation programs are accompanied by significant epigenetic remodeling where DNA methylation associates with cell identity. Here we show that DNA methylation changes characteristic for monocyte-to-macrophage differentiation occur at transcription factor binding sites, and, in contrast to what was previously described, are generally highly localized and encompass both losses and gains of DNA methylation. Results We compared genome-wide DNA methylation across 440,292 CpG sites between human monocytes, naïve macrophages and macrophages further activated toward a pro-inflammatory state (using LPS/IFNγ), an anti-inflammatory state (IL-4) or foam cells (oxLDL and acLDL). Moreover, we integrated these data with public whole-genome sequencing data on monocytes and macrophages to demarcate differentially methylated regions. Our analysis showed that differential DNA methylation was most pronounced during monocyte-to-macrophage differentiation, was typically restricted to single CpGs or very short regions, and co-localized with lineage-specific enhancers irrespective of whether it concerns gain or loss of methylation. Furthermore, differentially methylated CpGs were located at sites characterized by increased binding of transcription factors known to be involved in monocyte-to-macrophage differentiation including C/EBP and ETS for gain and AP-1 for loss of methylation. Conclusion Our study highlights the involvement of subtle, yet highly localized remodeling of DNA methylation at regulatory regions in cell differentiation.http://link.springer.com/article/10.1186/s13072-019-0279-4DNA methylationDifferentiationEpigenomicsMacrophageMonocyteTranscription factor |
| spellingShingle | Koen F. Dekkers Annette E. Neele J. Wouter Jukema Bastiaan T. Heijmans Menno P. J. de Winther Human monocyte-to-macrophage differentiation involves highly localized gain and loss of DNA methylation at transcription factor binding sites Epigenetics & Chromatin DNA methylation Differentiation Epigenomics Macrophage Monocyte Transcription factor |
| title | Human monocyte-to-macrophage differentiation involves highly localized gain and loss of DNA methylation at transcription factor binding sites |
| title_full | Human monocyte-to-macrophage differentiation involves highly localized gain and loss of DNA methylation at transcription factor binding sites |
| title_fullStr | Human monocyte-to-macrophage differentiation involves highly localized gain and loss of DNA methylation at transcription factor binding sites |
| title_full_unstemmed | Human monocyte-to-macrophage differentiation involves highly localized gain and loss of DNA methylation at transcription factor binding sites |
| title_short | Human monocyte-to-macrophage differentiation involves highly localized gain and loss of DNA methylation at transcription factor binding sites |
| title_sort | human monocyte to macrophage differentiation involves highly localized gain and loss of dna methylation at transcription factor binding sites |
| topic | DNA methylation Differentiation Epigenomics Macrophage Monocyte Transcription factor |
| url | http://link.springer.com/article/10.1186/s13072-019-0279-4 |
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