Details

Autor(en) / Beteiligte

• Qin, Kunhua
• Lan, Xianjiang
• Huang, Peng
• Saari, Megan S.
• Khandros, Eugene
• Keller, Cheryl A.
• Giardine, Belinda
• Abdulmalik, Osheiza
• Shi, Junwei
• Hardison, Ross C.
• Blobel, Gerd A.

Titel

Molecular basis of polycomb group protein–mediated fetal hemoglobin repression

Ist Teil von

• Blood, 2023-06, Vol.141 (22), p.2756-2770

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2023

Quelle

MEDLINE

Beschreibungen/Notizen

• •A CRISPR screen for HbF repressors identified polycomb protein BMI1, which is found to function within the canonical PRC1 complex.•RNA binding proteins LIN28B, IGF2BP1, and IGF2BP3 are the critical links between PRC1 and HbF repression in adult-type erythroid cells. [Display omitted] The switch from fetal hemoglobin (HbF) to adult hemoglobin (HbA) is a paradigm for developmental gene expression control with relevance to sickle cell disease and β-thalassemia. Polycomb repressive complex (PRC) proteins regulate this switch, and an inhibitor of PRC2 has entered a clinical trial for HbF activation. Yet, how PRC complexes function in this process, their target genes, and relevant subunit composition are unknown. Here, we identified the PRC1 subunit BMI1 as a novel HbF repressor. We uncovered the RNA binding proteins LIN28B, IGF2BP1, and IGF2BP3 genes as direct BMI1 targets, and demonstrate that they account for the entirety of BMI1’s effect on HbF regulation. BMI1 functions as part of the canonical PRC1 (cPRC1) subcomplex as revealed by the physical and functional dissection of BMI1 protein partners. Lastly, we demonstrate that BMI1/cPRC1 acts in concert with PRC2 to repress HbF through the same target genes. Our study illuminates how PRC silences HbF, highlighting an epigenetic mechanism involved in hemoglobin switching.