TET2 binding to enhancers facilitates transcription factor recruitment in hematopoietic cells
The epigenetic regulator is frequently mutated in hematological diseases. Mutations have been shown to arise in hematopoietic stem cells early in disease development and lead to altered DNA methylation landscapes and an increased risk of hematopoietic malignancy. Here, we show by genome-wide mapping...
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| Veröffentlicht in: | Genome research 2019-04, Vol.29 (4), p.564-575 |
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| creator | Rasmussen, Kasper D Berest, Ivan Keβler, Sandra Nishimura, Koutarou Simón-Carrasco, Lucía Vassiliou, George S Pedersen, Marianne T Christensen, Jesper Zaugg, Judith B Helin, Kristian |
| description | The epigenetic regulator
is frequently mutated in hematological diseases. Mutations have been shown to arise in hematopoietic stem cells early in disease development and lead to altered DNA methylation landscapes and an increased risk of hematopoietic malignancy. Here, we show by genome-wide mapping of TET2 binding sites in different cell types that TET2 localizes to regions of open chromatin and cell-type-specific enhancers. We find that deletion of
in native hematopoiesis as well as fully transformed acute myeloid leukemia (AML) results in changes in transcription factor (TF) activity within these regions, and we provide evidence that loss of TET2 leads to attenuation of chromatin binding of members of the basic helix-loop-helix (bHLH) TF family. Together, these findings demonstrate that TET2 activity shapes the local chromatin environment at enhancers to facilitate TF binding and provides an example of how epigenetic dysregulation can affect gene expression patterns and drive disease development. |
| doi_str_mv | 10.1101/gr.239277.118 |
| format | Article |
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is frequently mutated in hematological diseases. Mutations have been shown to arise in hematopoietic stem cells early in disease development and lead to altered DNA methylation landscapes and an increased risk of hematopoietic malignancy. Here, we show by genome-wide mapping of TET2 binding sites in different cell types that TET2 localizes to regions of open chromatin and cell-type-specific enhancers. We find that deletion of
in native hematopoiesis as well as fully transformed acute myeloid leukemia (AML) results in changes in transcription factor (TF) activity within these regions, and we provide evidence that loss of TET2 leads to attenuation of chromatin binding of members of the basic helix-loop-helix (bHLH) TF family. Together, these findings demonstrate that TET2 activity shapes the local chromatin environment at enhancers to facilitate TF binding and provides an example of how epigenetic dysregulation can affect gene expression patterns and drive disease development.</description><identifier>ISSN: 1088-9051</identifier><identifier>EISSN: 1549-5469</identifier><identifier>DOI: 10.1101/gr.239277.118</identifier><identifier>PMID: 30796038</identifier><language>eng</language><publisher>United States: Cold Spring Harbor Laboratory Press</publisher><subject>Acute myeloid leukemia ; Animals ; Basic Helix-Loop-Helix Transcription Factors - metabolism ; Binding sites ; Cell Line ; Cells, Cultured ; Chromatin ; Chromatin - metabolism ; Dioxygenases ; DNA methylation ; DNA-Binding Proteins - metabolism ; Enhancer Elements, Genetic ; Enhancers ; Epigenesis, Genetic ; Epigenetics ; Gene expression ; Gene Expression Regulation, Neoplastic ; Gene mapping ; Genomes ; Hematological diseases ; Hematopoietic stem cells ; Hematopoietic Stem Cells - metabolism ; Leukemia, Myeloid, Acute - genetics ; Leukemia, Myeloid, Acute - metabolism ; Malignancy ; Mice ; Myeloid leukemia ; Protein Binding ; Proto-Oncogene Proteins - metabolism ; Stem cells ; Transcription factors</subject><ispartof>Genome research, 2019-04, Vol.29 (4), p.564-575</ispartof><rights>2019 Rasmussen et al.; Published by Cold Spring Harbor Laboratory Press.</rights><rights>Copyright Cold Spring Harbor Laboratory Press Apr 2019</rights><rights>2019</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c481t-dc7b1562cf35077f45aff01f90bb337c00f91888dca4691441a629cca42ea1b3</citedby><cites>FETCH-LOGICAL-c481t-dc7b1562cf35077f45aff01f90bb337c00f91888dca4691441a629cca42ea1b3</cites><orcidid>0000-0003-1975-6097 ; 0000-0001-8324-4040 ; 0000-0003-4337-8022</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6442383/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6442383/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,881,27901,27902,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/30796038$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Rasmussen, Kasper D</creatorcontrib><creatorcontrib>Berest, Ivan</creatorcontrib><creatorcontrib>Keβler, Sandra</creatorcontrib><creatorcontrib>Nishimura, Koutarou</creatorcontrib><creatorcontrib>Simón-Carrasco, Lucía</creatorcontrib><creatorcontrib>Vassiliou, George S</creatorcontrib><creatorcontrib>Pedersen, Marianne T</creatorcontrib><creatorcontrib>Christensen, Jesper</creatorcontrib><creatorcontrib>Zaugg, Judith B</creatorcontrib><creatorcontrib>Helin, Kristian</creatorcontrib><title>TET2 binding to enhancers facilitates transcription factor recruitment in hematopoietic cells</title><title>Genome research</title><addtitle>Genome Res</addtitle><description>The epigenetic regulator
is frequently mutated in hematological diseases. Mutations have been shown to arise in hematopoietic stem cells early in disease development and lead to altered DNA methylation landscapes and an increased risk of hematopoietic malignancy. Here, we show by genome-wide mapping of TET2 binding sites in different cell types that TET2 localizes to regions of open chromatin and cell-type-specific enhancers. We find that deletion of
in native hematopoiesis as well as fully transformed acute myeloid leukemia (AML) results in changes in transcription factor (TF) activity within these regions, and we provide evidence that loss of TET2 leads to attenuation of chromatin binding of members of the basic helix-loop-helix (bHLH) TF family. Together, these findings demonstrate that TET2 activity shapes the local chromatin environment at enhancers to facilitate TF binding and provides an example of how epigenetic dysregulation can affect gene expression patterns and drive disease development.</description><subject>Acute myeloid leukemia</subject><subject>Animals</subject><subject>Basic Helix-Loop-Helix Transcription Factors - metabolism</subject><subject>Binding sites</subject><subject>Cell Line</subject><subject>Cells, Cultured</subject><subject>Chromatin</subject><subject>Chromatin - metabolism</subject><subject>Dioxygenases</subject><subject>DNA methylation</subject><subject>DNA-Binding Proteins - metabolism</subject><subject>Enhancer Elements, Genetic</subject><subject>Enhancers</subject><subject>Epigenesis, Genetic</subject><subject>Epigenetics</subject><subject>Gene expression</subject><subject>Gene Expression Regulation, Neoplastic</subject><subject>Gene mapping</subject><subject>Genomes</subject><subject>Hematological diseases</subject><subject>Hematopoietic stem cells</subject><subject>Hematopoietic Stem Cells - metabolism</subject><subject>Leukemia, Myeloid, Acute - genetics</subject><subject>Leukemia, Myeloid, Acute - metabolism</subject><subject>Malignancy</subject><subject>Mice</subject><subject>Myeloid leukemia</subject><subject>Protein Binding</subject><subject>Proto-Oncogene Proteins - metabolism</subject><subject>Stem cells</subject><subject>Transcription factors</subject><issn>1088-9051</issn><issn>1549-5469</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpdkc1LHTEUxUOpVKsuuy2BbroZvfmYSbIpiNhaENy8rYRMXvJeZCZ5TTKC_33zeFa0q3sP98fhHg5CXwhcEALkcpMvKFNUiCblB3RCeq66ng_qY9tByk5BT47R51IeAYBxKT-hYwZCDcDkCXpY3awoHkNch7jBNWEXtyZalwv2xoYpVFNdwTWbWGwOuxpS3F9qyjg7m5dQZxcrDhFv3Wxq2qXgarDYumkqZ-jIm6m485d5ilY_b1bXt93d_a_f11d3neWS1G5txUj6gVrPehDC8954D8QrGEfGhAXwikgp19a0YIRzYgaqbFPUGTKyU_TjYLtbxtmtbXsom0nvcphNftbJBP3-EsNWb9KTHjinTLJm8P3FIKc_iytVz6HsE5jo0lI0JbLvB0HJ0NBv_6GPacmxpdOUglIKiJCN6g6UzamU7PzrMwT0vje9yfrQW5N7_uvbBK_0v6LYX5xWlTc</recordid><startdate>20190401</startdate><enddate>20190401</enddate><creator>Rasmussen, Kasper D</creator><creator>Berest, Ivan</creator><creator>Keβler, Sandra</creator><creator>Nishimura, Koutarou</creator><creator>Simón-Carrasco, Lucía</creator><creator>Vassiliou, George S</creator><creator>Pedersen, Marianne T</creator><creator>Christensen, Jesper</creator><creator>Zaugg, Judith B</creator><creator>Helin, Kristian</creator><general>Cold Spring Harbor Laboratory Press</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7TM</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0003-1975-6097</orcidid><orcidid>https://orcid.org/0000-0001-8324-4040</orcidid><orcidid>https://orcid.org/0000-0003-4337-8022</orcidid></search><sort><creationdate>20190401</creationdate><title>TET2 binding to enhancers facilitates transcription factor recruitment in hematopoietic cells</title><author>Rasmussen, Kasper D ; Berest, Ivan ; Keβler, Sandra ; Nishimura, Koutarou ; Simón-Carrasco, Lucía ; Vassiliou, George S ; Pedersen, Marianne T ; Christensen, Jesper ; Zaugg, Judith B ; Helin, Kristian</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c481t-dc7b1562cf35077f45aff01f90bb337c00f91888dca4691441a629cca42ea1b3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>Acute myeloid leukemia</topic><topic>Animals</topic><topic>Basic Helix-Loop-Helix Transcription Factors - metabolism</topic><topic>Binding sites</topic><topic>Cell Line</topic><topic>Cells, Cultured</topic><topic>Chromatin</topic><topic>Chromatin - metabolism</topic><topic>Dioxygenases</topic><topic>DNA methylation</topic><topic>DNA-Binding Proteins - metabolism</topic><topic>Enhancer Elements, Genetic</topic><topic>Enhancers</topic><topic>Epigenesis, Genetic</topic><topic>Epigenetics</topic><topic>Gene expression</topic><topic>Gene Expression Regulation, Neoplastic</topic><topic>Gene mapping</topic><topic>Genomes</topic><topic>Hematological diseases</topic><topic>Hematopoietic stem cells</topic><topic>Hematopoietic Stem Cells - metabolism</topic><topic>Leukemia, Myeloid, Acute - genetics</topic><topic>Leukemia, Myeloid, Acute - metabolism</topic><topic>Malignancy</topic><topic>Mice</topic><topic>Myeloid leukemia</topic><topic>Protein Binding</topic><topic>Proto-Oncogene Proteins - metabolism</topic><topic>Stem cells</topic><topic>Transcription factors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Rasmussen, Kasper D</creatorcontrib><creatorcontrib>Berest, Ivan</creatorcontrib><creatorcontrib>Keβler, Sandra</creatorcontrib><creatorcontrib>Nishimura, Koutarou</creatorcontrib><creatorcontrib>Simón-Carrasco, Lucía</creatorcontrib><creatorcontrib>Vassiliou, George S</creatorcontrib><creatorcontrib>Pedersen, Marianne T</creatorcontrib><creatorcontrib>Christensen, Jesper</creatorcontrib><creatorcontrib>Zaugg, Judith B</creatorcontrib><creatorcontrib>Helin, Kristian</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Nucleic Acids Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Genome research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Rasmussen, Kasper D</au><au>Berest, Ivan</au><au>Keβler, Sandra</au><au>Nishimura, Koutarou</au><au>Simón-Carrasco, Lucía</au><au>Vassiliou, George S</au><au>Pedersen, Marianne T</au><au>Christensen, Jesper</au><au>Zaugg, Judith B</au><au>Helin, Kristian</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>TET2 binding to enhancers facilitates transcription factor recruitment in hematopoietic cells</atitle><jtitle>Genome research</jtitle><addtitle>Genome Res</addtitle><date>2019-04-01</date><risdate>2019</risdate><volume>29</volume><issue>4</issue><spage>564</spage><epage>575</epage><pages>564-575</pages><issn>1088-9051</issn><eissn>1549-5469</eissn><abstract>The epigenetic regulator
is frequently mutated in hematological diseases. Mutations have been shown to arise in hematopoietic stem cells early in disease development and lead to altered DNA methylation landscapes and an increased risk of hematopoietic malignancy. Here, we show by genome-wide mapping of TET2 binding sites in different cell types that TET2 localizes to regions of open chromatin and cell-type-specific enhancers. We find that deletion of
in native hematopoiesis as well as fully transformed acute myeloid leukemia (AML) results in changes in transcription factor (TF) activity within these regions, and we provide evidence that loss of TET2 leads to attenuation of chromatin binding of members of the basic helix-loop-helix (bHLH) TF family. Together, these findings demonstrate that TET2 activity shapes the local chromatin environment at enhancers to facilitate TF binding and provides an example of how epigenetic dysregulation can affect gene expression patterns and drive disease development.</abstract><cop>United States</cop><pub>Cold Spring Harbor Laboratory Press</pub><pmid>30796038</pmid><doi>10.1101/gr.239277.118</doi><tpages>12</tpages><orcidid>https://orcid.org/0000-0003-1975-6097</orcidid><orcidid>https://orcid.org/0000-0001-8324-4040</orcidid><orcidid>https://orcid.org/0000-0003-4337-8022</orcidid><oa>free_for_read</oa></addata></record> |
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| ispartof | Genome research, 2019-04, Vol.29 (4), p.564-575 |
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| subjects | Acute myeloid leukemia Animals Basic Helix-Loop-Helix Transcription Factors - metabolism Binding sites Cell Line Cells, Cultured Chromatin Chromatin - metabolism Dioxygenases DNA methylation DNA-Binding Proteins - metabolism Enhancer Elements, Genetic Enhancers Epigenesis, Genetic Epigenetics Gene expression Gene Expression Regulation, Neoplastic Gene mapping Genomes Hematological diseases Hematopoietic stem cells Hematopoietic Stem Cells - metabolism Leukemia, Myeloid, Acute - genetics Leukemia, Myeloid, Acute - metabolism Malignancy Mice Myeloid leukemia Protein Binding Proto-Oncogene Proteins - metabolism Stem cells Transcription factors |
| title | TET2 binding to enhancers facilitates transcription factor recruitment in hematopoietic cells |
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