The Human TET2 Gene Contains Three Distinct Promoter Regions With Differing Tissue and Developmental Specificities
Tet methylcytosine dioxygenase 2 (TET2) is a tumor suppressor gene that is inactivated in a wide range of hematological cancers. TET2 enzymatic activity converts 5-methylcytosine (5-mC) into 5-hydroxymethylcytosine (5-hmC), an essential step in DNA demethylation. Human TET2 is highly expressed in pl...
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2019-06-01
|
| Series: | Frontiers in Cell and Developmental Biology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/article/10.3389/fcell.2019.00099/full |
| _version_ | 1819162254965211136 |
|---|---|
| author | Hong Lou Hongchuan Li Kevin J. Ho Luke L. Cai Andy S. Huang Tyler R. Shank Michael R. Verneris Michael L. Nickerson Michael Dean Stephen K. Anderson Stephen K. Anderson |
| author_facet | Hong Lou Hongchuan Li Kevin J. Ho Luke L. Cai Andy S. Huang Tyler R. Shank Michael R. Verneris Michael L. Nickerson Michael Dean Stephen K. Anderson Stephen K. Anderson |
| author_sort | Hong Lou |
| collection | DOAJ |
| description | Tet methylcytosine dioxygenase 2 (TET2) is a tumor suppressor gene that is inactivated in a wide range of hematological cancers. TET2 enzymatic activity converts 5-methylcytosine (5-mC) into 5-hydroxymethylcytosine (5-hmC), an essential step in DNA demethylation. Human TET2 is highly expressed in pluripotent cells and down-regulated in differentiated cells: however, transcriptional regulation of the human TET2 gene has not been investigated in detail. Here we define three promoters within a 2.5 kb region located ∼ 87 kb upstream of the first TET2 coding exon. The three promoters, designated as Pro1, Pro2, and Pro3, generate three alternative first exons, and their presence in TET2 mRNAs varies with cell type and developmental stage. In general, all three TET2 transcripts are more highly expressed in human tissues rich in hematopoietic stem cells, such as spleen and bone marrow, compared to other tissues, such as brain and kidney. Transcripts from Pro2 are expressed by a broad range of tissues and at a significantly higher level than Pro1 or Pro3 transcripts. Pro3 transcripts were highly expressed by embryoid bodies generated from the H9 ES cell line, and the major Pro3 transcript is an alternatively spliced mRNA isoform that produces a truncated TET2 protein lacking the catalytic domain. Our study demonstrates distinct tissue-specific mechanisms of TET2 transcriptional regulation during early pluripotent states and in differentiated cell types. |
| first_indexed | 2024-12-22T17:25:19Z |
| format | Article |
| id | doaj.art-96b99fbd34af4bcb9e2300a3abdfafad |
| institution | Directory Open Access Journal |
| issn | 2296-634X |
| language | English |
| last_indexed | 2024-12-22T17:25:19Z |
| publishDate | 2019-06-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Cell and Developmental Biology |
| spelling | doaj.art-96b99fbd34af4bcb9e2300a3abdfafad2022-12-21T18:18:44ZengFrontiers Media S.A.Frontiers in Cell and Developmental Biology2296-634X2019-06-01710.3389/fcell.2019.00099455748The Human TET2 Gene Contains Three Distinct Promoter Regions With Differing Tissue and Developmental SpecificitiesHong Lou0Hongchuan Li1Kevin J. Ho2Luke L. Cai3Andy S. Huang4Tyler R. Shank5Michael R. Verneris6Michael L. Nickerson7Michael Dean8Stephen K. Anderson9Stephen K. Anderson10Laboratory of Translational Genomics, Frederick National Laboratory for Cancer Research, Gaithersburg, MD, United StatesBasic Science Program, Frederick National Laboratory for Cancer Research, Frederick, MD, United StatesCancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, MD, United StatesCancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, MD, United StatesCancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, MD, United StatesDepartment of Pediatrics, Center for Cancer and Blood Disorders, University of Colorado Denver, Denver, CO, United StatesDepartment of Pediatrics, Center for Cancer and Blood Disorders, University of Colorado Denver, Denver, CO, United StatesLaboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Gaithersburg, MD, United StatesLaboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Gaithersburg, MD, United StatesBasic Science Program, Frederick National Laboratory for Cancer Research, Frederick, MD, United StatesCancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, MD, United StatesTet methylcytosine dioxygenase 2 (TET2) is a tumor suppressor gene that is inactivated in a wide range of hematological cancers. TET2 enzymatic activity converts 5-methylcytosine (5-mC) into 5-hydroxymethylcytosine (5-hmC), an essential step in DNA demethylation. Human TET2 is highly expressed in pluripotent cells and down-regulated in differentiated cells: however, transcriptional regulation of the human TET2 gene has not been investigated in detail. Here we define three promoters within a 2.5 kb region located ∼ 87 kb upstream of the first TET2 coding exon. The three promoters, designated as Pro1, Pro2, and Pro3, generate three alternative first exons, and their presence in TET2 mRNAs varies with cell type and developmental stage. In general, all three TET2 transcripts are more highly expressed in human tissues rich in hematopoietic stem cells, such as spleen and bone marrow, compared to other tissues, such as brain and kidney. Transcripts from Pro2 are expressed by a broad range of tissues and at a significantly higher level than Pro1 or Pro3 transcripts. Pro3 transcripts were highly expressed by embryoid bodies generated from the H9 ES cell line, and the major Pro3 transcript is an alternatively spliced mRNA isoform that produces a truncated TET2 protein lacking the catalytic domain. Our study demonstrates distinct tissue-specific mechanisms of TET2 transcriptional regulation during early pluripotent states and in differentiated cell types.https://www.frontiersin.org/article/10.3389/fcell.2019.00099/fullhumanTET2alternative promotersdemethylationdifferentiationmRNA isoforms |
| spellingShingle | Hong Lou Hongchuan Li Kevin J. Ho Luke L. Cai Andy S. Huang Tyler R. Shank Michael R. Verneris Michael L. Nickerson Michael Dean Stephen K. Anderson Stephen K. Anderson The Human TET2 Gene Contains Three Distinct Promoter Regions With Differing Tissue and Developmental Specificities Frontiers in Cell and Developmental Biology human TET2 alternative promoters demethylation differentiation mRNA isoforms |
| title | The Human TET2 Gene Contains Three Distinct Promoter Regions With Differing Tissue and Developmental Specificities |
| title_full | The Human TET2 Gene Contains Three Distinct Promoter Regions With Differing Tissue and Developmental Specificities |
| title_fullStr | The Human TET2 Gene Contains Three Distinct Promoter Regions With Differing Tissue and Developmental Specificities |
| title_full_unstemmed | The Human TET2 Gene Contains Three Distinct Promoter Regions With Differing Tissue and Developmental Specificities |
| title_short | The Human TET2 Gene Contains Three Distinct Promoter Regions With Differing Tissue and Developmental Specificities |
| title_sort | human tet2 gene contains three distinct promoter regions with differing tissue and developmental specificities |
| topic | human TET2 alternative promoters demethylation differentiation mRNA isoforms |
| url | https://www.frontiersin.org/article/10.3389/fcell.2019.00099/full |
| work_keys_str_mv | AT honglou thehumantet2genecontainsthreedistinctpromoterregionswithdifferingtissueanddevelopmentalspecificities AT hongchuanli thehumantet2genecontainsthreedistinctpromoterregionswithdifferingtissueanddevelopmentalspecificities AT kevinjho thehumantet2genecontainsthreedistinctpromoterregionswithdifferingtissueanddevelopmentalspecificities AT lukelcai thehumantet2genecontainsthreedistinctpromoterregionswithdifferingtissueanddevelopmentalspecificities AT andyshuang thehumantet2genecontainsthreedistinctpromoterregionswithdifferingtissueanddevelopmentalspecificities AT tylerrshank thehumantet2genecontainsthreedistinctpromoterregionswithdifferingtissueanddevelopmentalspecificities AT michaelrverneris thehumantet2genecontainsthreedistinctpromoterregionswithdifferingtissueanddevelopmentalspecificities AT michaellnickerson thehumantet2genecontainsthreedistinctpromoterregionswithdifferingtissueanddevelopmentalspecificities AT michaeldean thehumantet2genecontainsthreedistinctpromoterregionswithdifferingtissueanddevelopmentalspecificities AT stephenkanderson thehumantet2genecontainsthreedistinctpromoterregionswithdifferingtissueanddevelopmentalspecificities AT stephenkanderson thehumantet2genecontainsthreedistinctpromoterregionswithdifferingtissueanddevelopmentalspecificities AT honglou humantet2genecontainsthreedistinctpromoterregionswithdifferingtissueanddevelopmentalspecificities AT hongchuanli humantet2genecontainsthreedistinctpromoterregionswithdifferingtissueanddevelopmentalspecificities AT kevinjho humantet2genecontainsthreedistinctpromoterregionswithdifferingtissueanddevelopmentalspecificities AT lukelcai humantet2genecontainsthreedistinctpromoterregionswithdifferingtissueanddevelopmentalspecificities AT andyshuang humantet2genecontainsthreedistinctpromoterregionswithdifferingtissueanddevelopmentalspecificities AT tylerrshank humantet2genecontainsthreedistinctpromoterregionswithdifferingtissueanddevelopmentalspecificities AT michaelrverneris humantet2genecontainsthreedistinctpromoterregionswithdifferingtissueanddevelopmentalspecificities AT michaellnickerson humantet2genecontainsthreedistinctpromoterregionswithdifferingtissueanddevelopmentalspecificities AT michaeldean humantet2genecontainsthreedistinctpromoterregionswithdifferingtissueanddevelopmentalspecificities AT stephenkanderson humantet2genecontainsthreedistinctpromoterregionswithdifferingtissueanddevelopmentalspecificities AT stephenkanderson humantet2genecontainsthreedistinctpromoterregionswithdifferingtissueanddevelopmentalspecificities |