Division of Hematology, Children's Hospital of Philadelphia, Philadelphia, PA.
Department of Systems Biology for Medicine, School of Basic Medical Sciences, Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China.
Blood. 2023 Jun 1;141(22):2756-2770. doi: 10.1182/blood.2022019578.
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.
从胎儿血红蛋白 (HbF) 转变为成人血红蛋白 (HbA) 是发育基因表达调控的典范，与镰状细胞病和 β-地中海贫血有关。多梳抑制复合物 (PRC) 蛋白调节这种转变，PRC2 的抑制剂已进入 HbF 激活的临床试验。然而，PRC 复合物在这个过程中的作用、它们的靶基因和相关亚基组成尚不清楚。在这里，我们确定了 PRC1 亚基 BMI1 是 HbF 的新型抑制因子。我们发现 RNA 结合蛋白 LIN28B、IGF2BP1 和 IGF2BP3 基因是 BMI1 的直接靶基因，并证明它们解释了 BMI1 对 HbF 调节的全部影响。BMI1 作为经典 PRC1 (cPRC1) 亚复合物的一部分发挥作用，这是通过 BMI1 蛋白伙伴的物理和功能剖析揭示的。最后，我们证明 BMI1/cPRC1 通过相同的靶基因与 PRC2 协同作用来抑制 HbF。我们的研究阐明了 PRC 如何沉默 HbF，强调了参与血红蛋白转换的表观遗传机制。
