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Allogeneic haematopoietic stem cell transplantation, the only curative therapy, is only applied to a small minority of patients. Common clinical management strategies act mainly downstream of the root causes of disease. The observation that elevated fetal haemoglobin expression ameliorates these disorders has motivated longstanding investigations into the mechanisms of haemoglobin switching. Landmark studies over the last decade have led to the identification of two potent transcriptional repressors of \u03b3\u2010globin, <jats:styled-content style=\"fixed-case\">BCL<\/jats:styled-content>11A and <jats:styled-content style=\"fixed-case\">ZBTB<\/jats:styled-content>7A. These regulators act with additional <jats:italic>trans<\/jats:italic>\u2010acting epigenetic repressive complexes, lineage\u2010defining factors and developmental programs to silence fetal haemoglobin by working on <jats:italic>cis<\/jats:italic>\u2010acting sequences at the globin gene loci. Rapidly advancing genetic technology is enabling researchers to probe deeply the interplay between the molecular players required for \u03b3\u2010globin (<jats:italic><jats:styled-content style=\"fixed-case\">HBG<\/jats:styled-content>1\/<jats:styled-content style=\"fixed-case\">HBG<\/jats:styled-content>2<\/jats:italic>) silencing. Gene therapies may enable permanent cures with autologous modified haematopoietic stem cells that generate persistent fetal haemoglobin expression. Ultimately rational small molecule pharmacotherapies to reactivate HbF could extend benefits widely to patients.<\/jats:p>","DOI":"10.1111\/bjh.15038","type":"journal-article","created":{"date-parts":[[2017,11,29]],"date-time":"2017-11-29T15:39:45Z","timestamp":1511969985000},"page":"630-643","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":114,"title":["Recent progress in understanding and manipulating haemoglobin switching for the haemoglobinopathies"],"prefix":"10.1111","volume":"180","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9369-0412","authenticated-orcid":false,"given":"Divya S.","family":"Vinjamur","sequence":"first","affiliation":[{"name":"Boston Children's Hospital Boston MA USA"},{"name":"Harvard Medical School Boston MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel E.","family":"Bauer","sequence":"additional","affiliation":[{"name":"Boston Children's Hospital Boston MA USA"},{"name":"Harvard Medical School Boston MA USA"},{"name":"Dana\u2010Farber Cancer Institute Boston MA USA"},{"name":"Harvard Stem Cell Institute Cambridge MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stuart H.","family":"Orkin","sequence":"additional","affiliation":[{"name":"Boston Children's Hospital Boston MA USA"},{"name":"Harvard Medical School Boston MA USA"},{"name":"Dana\u2010Farber Cancer Institute Boston MA USA"},{"name":"Harvard Stem Cell Institute Cambridge MA USA"},{"name":"Howard Hughes Medical Institute Boston MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2017,11,28]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2012-11-466227"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.3324\/haematol.2013.099747"},{"key":"e_1_2_8_4_1","first-page":"421","article-title":"Induction of erythroid\u2010specific expression in murine erythroleukemia (MEL) cell lines","volume":"7","author":"Antoniou M.","year":"1991","journal-title":"Methods in Molecular Biology"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2010.10.010"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI81163"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-2836(77)80068-5"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.gde.2015.08.001"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1242088"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.630"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2016-01-691089"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI87885"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature15521"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3793"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature09328"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.omtm.2016.12.009"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199505183322001"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0906769106"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1003155"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng0196-58"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2015-02-626259"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI101267"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1202332"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2012.03.051"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2014.05.050"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.79.14.4428"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature20134"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aaf9336"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2016.05.030"},{"key":"e_1_2_8_30_1","doi-asserted-by":"publisher","DOI":"10.1101\/gad.317004"},{"key":"e_1_2_8_31_1","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.25.12.5205-5214.2005"},{"key":"e_1_2_8_32_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2017-02-765891"},{"key":"e_1_2_8_33_1","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1182\/blood.V24.3.223.223","article-title":"Hereditary persistence of fetal hemoglobin in Greece. 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