HIC2 controls developmental hemoglobin switching by repressing BCL11A transcription
The fetal-to-adult switch in hemoglobin production is a model of developmental gene control with relevance to the treatment of hemoglobinopathies. The expression of transcription factor BCL11A, which represses fetal β-type globin ( HBG ) genes in adult erythroid cells, is predominantly controlled at...
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| Veröffentlicht in: | Nature genetics 2022-09, Vol.54 (9), p.1417-1426 |
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| creator | Huang, Peng Peslak, Scott A. Ren, Ren Khandros, Eugene Qin, Kunhua Keller, Cheryl A. Giardine, Belinda Bell, Henry W. Lan, Xianjiang Sharma, Malini Horton, John R. Abdulmalik, Osheiza Chou, Stella T. Shi, Junwei Crossley, Merlin Hardison, Ross C. Cheng, Xiaodong Blobel, Gerd A. |
| description | The fetal-to-adult switch in hemoglobin production is a model of developmental gene control with relevance to the treatment of hemoglobinopathies. The expression of transcription factor BCL11A, which represses fetal β-type globin (
HBG
) genes in adult erythroid cells, is predominantly controlled at the transcriptional level but the underlying mechanism is unclear. We identify HIC2 as a repressor of
BCL11A
transcription. HIC2 and BCL11A are reciprocally expressed during development. Forced expression of HIC2 in adult erythroid cells inhibits
BCL11A
transcription and induces
HBG
expression. HIC2 binds to erythroid
BCL11A
enhancers to reduce chromatin accessibility and binding of transcription factor GATA1, diminishing enhancer activity and enhancer–promoter contacts. DNA-binding and crystallography studies reveal direct steric hindrance as one mechanism by which HIC2 inhibits GATA1 binding at a critical
BCL11A
enhancer. Conversely, loss of HIC2 in fetal erythroblasts increases enhancer accessibility, GATA1 binding and
BCL11A
transcription. HIC2 emerges as an evolutionarily conserved regulator of hemoglobin switching via developmental control of
BCL11A
.
HIC2 regulates the fetal-to-adult hemoglobin switch. It inactivates an enhancer of the
BCL11A
gene, a fetal globin repressor, by reducing chromatin accessibility and displacing the transcription factor GATA1. |
| doi_str_mv | 10.1038/s41588-022-01152-6 |
| format | Article |
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HBG
) genes in adult erythroid cells, is predominantly controlled at the transcriptional level but the underlying mechanism is unclear. We identify HIC2 as a repressor of
BCL11A
transcription. HIC2 and BCL11A are reciprocally expressed during development. Forced expression of HIC2 in adult erythroid cells inhibits
BCL11A
transcription and induces
HBG
expression. HIC2 binds to erythroid
BCL11A
enhancers to reduce chromatin accessibility and binding of transcription factor GATA1, diminishing enhancer activity and enhancer–promoter contacts. DNA-binding and crystallography studies reveal direct steric hindrance as one mechanism by which HIC2 inhibits GATA1 binding at a critical
BCL11A
enhancer. Conversely, loss of HIC2 in fetal erythroblasts increases enhancer accessibility, GATA1 binding and
BCL11A
transcription. HIC2 emerges as an evolutionarily conserved regulator of hemoglobin switching via developmental control of
BCL11A
.
HIC2 regulates the fetal-to-adult hemoglobin switch. It inactivates an enhancer of the
BCL11A
gene, a fetal globin repressor, by reducing chromatin accessibility and displacing the transcription factor GATA1.</description><identifier>ISSN: 1061-4036</identifier><identifier>ISSN: 1546-1718</identifier><identifier>EISSN: 1546-1718</identifier><identifier>DOI: 10.1038/s41588-022-01152-6</identifier><identifier>PMID: 35941187</identifier><language>eng</language><publisher>New York: Nature Publishing Group US</publisher><subject>631/208/200 ; 631/337/176 ; 692/699/1541 ; Accessibility ; Agriculture ; Animal Genetics and Genomics ; beta-Globins - genetics ; beta-Globins - metabolism ; Binding ; Biomedical and Life Sciences ; Biomedicine ; Blood diseases ; Cancer Research ; Carrier Proteins - genetics ; Chromatin ; CRISPR ; Crystallography ; Enhancers ; Erythroblasts ; Erythroid cells ; Erythroid Cells - metabolism ; Fetuses ; gamma-Globins - genetics ; GATA-1 protein ; Gene expression ; Gene Function ; Hemoglobin ; Hemoglobins - genetics ; Human Genetics ; Humans ; Kruppel-Like Transcription Factors - metabolism ; Proteins ; Repressor Proteins - genetics ; Repressor Proteins - metabolism ; RNA polymerase ; Steric hindrance ; Transcription factors ; Transcription Factors - genetics ; Transcription Factors - metabolism ; Tumor Suppressor Proteins - metabolism</subject><ispartof>Nature genetics, 2022-09, Vol.54 (9), p.1417-1426</ispartof><rights>The Author(s), under exclusive licence to Springer Nature America, Inc. 2022. corrected publication 2023. Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.</rights><rights>2022. The Author(s), under exclusive licence to Springer Nature America, Inc.</rights><rights>Copyright Nature Publishing Group Sep 2022</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c474t-70f3b227b93e9247b6b55bc9893af6387e52da902103bf56246e07e1259f40393</citedby><cites>FETCH-LOGICAL-c474t-70f3b227b93e9247b6b55bc9893af6387e52da902103bf56246e07e1259f40393</cites><orcidid>0000-0003-4333-6965 ; 0000-0003-4084-7516 ; 0000-0002-0714-9612 ; 0000-0003-3008-851X ; 0000-0001-8458-4995 ; 0000-0003-2057-3642 ; 0000-0001-6594-0245 ; 0000-0003-4677-8208 ; 0000-0003-2497-4291 ; 0000-0003-1483-1545 ; 0000-0002-8427-6316 ; 0000-0002-4681-1074 ; 0000-0002-6967-6362</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,780,784,885,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/35941187$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Huang, Peng</creatorcontrib><creatorcontrib>Peslak, Scott A.</creatorcontrib><creatorcontrib>Ren, Ren</creatorcontrib><creatorcontrib>Khandros, Eugene</creatorcontrib><creatorcontrib>Qin, Kunhua</creatorcontrib><creatorcontrib>Keller, Cheryl A.</creatorcontrib><creatorcontrib>Giardine, Belinda</creatorcontrib><creatorcontrib>Bell, Henry W.</creatorcontrib><creatorcontrib>Lan, Xianjiang</creatorcontrib><creatorcontrib>Sharma, Malini</creatorcontrib><creatorcontrib>Horton, John R.</creatorcontrib><creatorcontrib>Abdulmalik, Osheiza</creatorcontrib><creatorcontrib>Chou, Stella T.</creatorcontrib><creatorcontrib>Shi, Junwei</creatorcontrib><creatorcontrib>Crossley, Merlin</creatorcontrib><creatorcontrib>Hardison, Ross C.</creatorcontrib><creatorcontrib>Cheng, Xiaodong</creatorcontrib><creatorcontrib>Blobel, Gerd A.</creatorcontrib><title>HIC2 controls developmental hemoglobin switching by repressing BCL11A transcription</title><title>Nature genetics</title><addtitle>Nat Genet</addtitle><addtitle>Nat Genet</addtitle><description>The fetal-to-adult switch in hemoglobin production is a model of developmental gene control with relevance to the treatment of hemoglobinopathies. The expression of transcription factor BCL11A, which represses fetal β-type globin (
HBG
) genes in adult erythroid cells, is predominantly controlled at the transcriptional level but the underlying mechanism is unclear. We identify HIC2 as a repressor of
BCL11A
transcription. HIC2 and BCL11A are reciprocally expressed during development. Forced expression of HIC2 in adult erythroid cells inhibits
BCL11A
transcription and induces
HBG
expression. HIC2 binds to erythroid
BCL11A
enhancers to reduce chromatin accessibility and binding of transcription factor GATA1, diminishing enhancer activity and enhancer–promoter contacts. DNA-binding and crystallography studies reveal direct steric hindrance as one mechanism by which HIC2 inhibits GATA1 binding at a critical
BCL11A
enhancer. Conversely, loss of HIC2 in fetal erythroblasts increases enhancer accessibility, GATA1 binding and
BCL11A
transcription. HIC2 emerges as an evolutionarily conserved regulator of hemoglobin switching via developmental control of
BCL11A
.
HIC2 regulates the fetal-to-adult hemoglobin switch. It inactivates an enhancer of the
BCL11A
gene, a fetal globin repressor, by reducing chromatin accessibility and displacing the transcription factor GATA1.</description><subject>631/208/200</subject><subject>631/337/176</subject><subject>692/699/1541</subject><subject>Accessibility</subject><subject>Agriculture</subject><subject>Animal Genetics and Genomics</subject><subject>beta-Globins - genetics</subject><subject>beta-Globins - metabolism</subject><subject>Binding</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedicine</subject><subject>Blood diseases</subject><subject>Cancer Research</subject><subject>Carrier Proteins - genetics</subject><subject>Chromatin</subject><subject>CRISPR</subject><subject>Crystallography</subject><subject>Enhancers</subject><subject>Erythroblasts</subject><subject>Erythroid cells</subject><subject>Erythroid Cells - metabolism</subject><subject>Fetuses</subject><subject>gamma-Globins - genetics</subject><subject>GATA-1 protein</subject><subject>Gene expression</subject><subject>Gene Function</subject><subject>Hemoglobin</subject><subject>Hemoglobins - genetics</subject><subject>Human Genetics</subject><subject>Humans</subject><subject>Kruppel-Like Transcription Factors - metabolism</subject><subject>Proteins</subject><subject>Repressor Proteins - genetics</subject><subject>Repressor Proteins - metabolism</subject><subject>RNA polymerase</subject><subject>Steric hindrance</subject><subject>Transcription factors</subject><subject>Transcription Factors - genetics</subject><subject>Transcription Factors - metabolism</subject><subject>Tumor Suppressor Proteins - metabolism</subject><issn>1061-4036</issn><issn>1546-1718</issn><issn>1546-1718</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>8G5</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNp9kU9P3DAQxa0KVCjtF-ihisSll4DH_31BoqsWkFbqoe3ZsrPOrlFip3aWim9f0wUKHDiNR_Ob53l6CH0EfAKYqtPCgCvVYkJaDMBJK96gQ-BMtCBB7dU3FtAyTMUBelfKNcbAGFZv0QHlmgEoeYh-XF4tSNOlOOc0lGblb_yQptHH2Q7Nxo9pPSQXYlP-hLnbhLhu3G2T_ZR9KXfdl8US4LyZs42ly2GaQ4rv0X5vh-I_3Ncj9Ovb15-Ly3b5_eJqcb5sOybZ3ErcU0eIdJp6TZh0wnHuOq00tb2gSnpOVlZjUs26ngvChMfSA-G6r6Y0PUJnO91p60a_6urR2Q5mymG0-dYkG8zzSQwbs043RmuGBWVV4PO9QE6_t77MZgyl88Ngo0_bYojEmAITilf0-AV6nbY5VnuGAmHAqgFaKbKjupxKyb5_PAawucvM7DIzNTPzLzMj6tKnpzYeVx5CqgDdAaWO4trn_3-_IvsXCSChbQ</recordid><startdate>20220901</startdate><enddate>20220901</enddate><creator>Huang, 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controls developmental hemoglobin switching by repressing BCL11A transcription</title><author>Huang, Peng ; Peslak, Scott A. ; Ren, Ren ; Khandros, Eugene ; Qin, Kunhua ; Keller, Cheryl A. ; Giardine, Belinda ; Bell, Henry W. ; Lan, Xianjiang ; Sharma, Malini ; Horton, John R. ; Abdulmalik, Osheiza ; Chou, Stella T. ; Shi, Junwei ; Crossley, Merlin ; Hardison, Ross C. ; Cheng, Xiaodong ; Blobel, Gerd A.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c474t-70f3b227b93e9247b6b55bc9893af6387e52da902103bf56246e07e1259f40393</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2022</creationdate><topic>631/208/200</topic><topic>631/337/176</topic><topic>692/699/1541</topic><topic>Accessibility</topic><topic>Agriculture</topic><topic>Animal Genetics and Genomics</topic><topic>beta-Globins - genetics</topic><topic>beta-Globins - metabolism</topic><topic>Binding</topic><topic>Biomedical and Life Sciences</topic><topic>Biomedicine</topic><topic>Blood diseases</topic><topic>Cancer Research</topic><topic>Carrier Proteins - genetics</topic><topic>Chromatin</topic><topic>CRISPR</topic><topic>Crystallography</topic><topic>Enhancers</topic><topic>Erythroblasts</topic><topic>Erythroid cells</topic><topic>Erythroid Cells - metabolism</topic><topic>Fetuses</topic><topic>gamma-Globins - genetics</topic><topic>GATA-1 protein</topic><topic>Gene expression</topic><topic>Gene Function</topic><topic>Hemoglobin</topic><topic>Hemoglobins - genetics</topic><topic>Human Genetics</topic><topic>Humans</topic><topic>Kruppel-Like Transcription Factors - metabolism</topic><topic>Proteins</topic><topic>Repressor Proteins - genetics</topic><topic>Repressor Proteins - metabolism</topic><topic>RNA polymerase</topic><topic>Steric hindrance</topic><topic>Transcription factors</topic><topic>Transcription Factors - genetics</topic><topic>Transcription Factors - metabolism</topic><topic>Tumor Suppressor Proteins - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Huang, Peng</creatorcontrib><creatorcontrib>Peslak, Scott A.</creatorcontrib><creatorcontrib>Ren, Ren</creatorcontrib><creatorcontrib>Khandros, Eugene</creatorcontrib><creatorcontrib>Qin, Kunhua</creatorcontrib><creatorcontrib>Keller, Cheryl A.</creatorcontrib><creatorcontrib>Giardine, Belinda</creatorcontrib><creatorcontrib>Bell, Henry W.</creatorcontrib><creatorcontrib>Lan, Xianjiang</creatorcontrib><creatorcontrib>Sharma, Malini</creatorcontrib><creatorcontrib>Horton, John R.</creatorcontrib><creatorcontrib>Abdulmalik, Osheiza</creatorcontrib><creatorcontrib>Chou, Stella T.</creatorcontrib><creatorcontrib>Shi, Junwei</creatorcontrib><creatorcontrib>Crossley, Merlin</creatorcontrib><creatorcontrib>Hardison, Ross C.</creatorcontrib><creatorcontrib>Cheng, Xiaodong</creatorcontrib><creatorcontrib>Blobel, Gerd 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A.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>HIC2 controls developmental hemoglobin switching by repressing BCL11A transcription</atitle><jtitle>Nature genetics</jtitle><stitle>Nat Genet</stitle><addtitle>Nat Genet</addtitle><date>2022-09-01</date><risdate>2022</risdate><volume>54</volume><issue>9</issue><spage>1417</spage><epage>1426</epage><pages>1417-1426</pages><issn>1061-4036</issn><issn>1546-1718</issn><eissn>1546-1718</eissn><abstract>The fetal-to-adult switch in hemoglobin production is a model of developmental gene control with relevance to the treatment of hemoglobinopathies. The expression of transcription factor BCL11A, which represses fetal β-type globin (
HBG
) genes in adult erythroid cells, is predominantly controlled at the transcriptional level but the underlying mechanism is unclear. We identify HIC2 as a repressor of
BCL11A
transcription. HIC2 and BCL11A are reciprocally expressed during development. Forced expression of HIC2 in adult erythroid cells inhibits
BCL11A
transcription and induces
HBG
expression. HIC2 binds to erythroid
BCL11A
enhancers to reduce chromatin accessibility and binding of transcription factor GATA1, diminishing enhancer activity and enhancer–promoter contacts. DNA-binding and crystallography studies reveal direct steric hindrance as one mechanism by which HIC2 inhibits GATA1 binding at a critical
BCL11A
enhancer. Conversely, loss of HIC2 in fetal erythroblasts increases enhancer accessibility, GATA1 binding and
BCL11A
transcription. HIC2 emerges as an evolutionarily conserved regulator of hemoglobin switching via developmental control of
BCL11A
.
HIC2 regulates the fetal-to-adult hemoglobin switch. It inactivates an enhancer of the
BCL11A
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| fulltext | fulltext |
| identifier | ISSN: 1061-4036 |
| ispartof | Nature genetics, 2022-09, Vol.54 (9), p.1417-1426 |
| issn | 1061-4036 1546-1718 1546-1718 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_9940634 |
| source | MEDLINE; Nature; Alma/SFX Local Collection |
| subjects | 631/208/200 631/337/176 692/699/1541 Accessibility Agriculture Animal Genetics and Genomics beta-Globins - genetics beta-Globins - metabolism Binding Biomedical and Life Sciences Biomedicine Blood diseases Cancer Research Carrier Proteins - genetics Chromatin CRISPR Crystallography Enhancers Erythroblasts Erythroid cells Erythroid Cells - metabolism Fetuses gamma-Globins - genetics GATA-1 protein Gene expression Gene Function Hemoglobin Hemoglobins - genetics Human Genetics Humans Kruppel-Like Transcription Factors - metabolism Proteins Repressor Proteins - genetics Repressor Proteins - metabolism RNA polymerase Steric hindrance Transcription factors Transcription Factors - genetics Transcription Factors - metabolism Tumor Suppressor Proteins - metabolism |
| title | HIC2 controls developmental hemoglobin switching by repressing BCL11A transcription |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-22T04%3A58%3A41IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=HIC2%20controls%20developmental%20hemoglobin%20switching%20by%20repressing%20BCL11A%20transcription&rft.jtitle=Nature%20genetics&rft.au=Huang,%20Peng&rft.date=2022-09-01&rft.volume=54&rft.issue=9&rft.spage=1417&rft.epage=1426&rft.pages=1417-1426&rft.issn=1061-4036&rft.eissn=1546-1718&rft_id=info:doi/10.1038/s41588-022-01152-6&rft_dat=%3Cproquest_pubme%3E3124142473%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=3124142473&rft_id=info:pmid/35941187&rfr_iscdi=true |