دورية أكاديمية
Identification of novel HPFH-like mutations by CRISPR base editing that elevate the expression of fetal hemoglobin
| العنوان: | Identification of novel HPFH-like mutations by CRISPR base editing that elevate the expression of fetal hemoglobin |
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| المؤلفون: | Nithin Sam Ravi, Beeke Wienert, Stacia K Wyman, Henry William Bell, Anila George, Gokulnath Mahalingam, Jonathan T Vu, Kirti Prasad, Bhanu Prasad Bandlamudi, Nivedhitha Devaraju, Vignesh Rajendiran, Nazar Syedbasha, Aswin Anand Pai, Yukio Nakamura, Ryo Kurita, Muthuraman Narayanasamy, Poonkuzhali Balasubramanian, Saravanabhavan Thangavel, Srujan Marepally, Shaji R Velayudhan, Alok Srivastava, Mark A DeWitt, Merlin Crossley, Jacob E Corn, Kumarasamypet M Mohankumar |
| المصدر: | eLife, Vol 11 (2022) |
| بيانات النشر: | eLife Sciences Publications Ltd, 2022. |
| سنة النشر: | 2022 |
| المجموعة: | LCC:Medicine LCC:Science LCC:Biology (General) |
| مصطلحات موضوعية: | base editing, globin regulation, HPFH mutations, beta-hemoglobinopathies, fetal hemoglobin, CRISPR/Cas9, Medicine, Science, Biology (General), QH301-705.5 |
| الوصف: | Naturally occurring point mutations in the HBG promoter switch hemoglobin synthesis from defective adult beta-globin to fetal gamma-globin in sickle cell patients with hereditary persistence of fetal hemoglobin (HPFH) and ameliorate the clinical severity. Inspired by this natural phenomenon, we tiled the highly homologous HBG proximal promoters using adenine and cytosine base editors that avoid the generation of large deletions and identified novel regulatory regions including a cluster at the –123 region. Base editing at –123 and –124 bp of HBG promoter induced fetal hemoglobin (HbF) to a higher level than disruption of well-known BCL11A binding site in erythroblasts derived from human CD34+ hematopoietic stem and progenitor cells (HSPC). We further demonstrated in vitro that the introduction of –123T > C and –124T > C HPFH-like mutations drives gamma-globin expression by creating a de novo binding site for KLF1. Overall, our findings shed light on so far unknown regulatory elements within the HBG promoter and identified additional targets for therapeutic upregulation of fetal hemoglobin. |
| نوع الوثيقة: | article |
| وصف الملف: | electronic resource |
| اللغة: | English |
| تدمد: | 2050-084X |
| العلاقة: | https://elifesciences.org/articles/65421Test; https://doaj.org/toc/2050-084XTest |
| DOI: | 10.7554/eLife.65421 |
| الوصول الحر: | https://doaj.org/article/4e7c9ae5baf449a09c47d7d306218410Test |
| رقم الانضمام: | edsdoj.4e7c9ae5baf449a09c47d7d306218410 |
| قاعدة البيانات: | Directory of Open Access Journals |
Full Text Finder | تدمد: | 2050084X |
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| DOI: | 10.7554/eLife.65421 |