美国宾夕法尼亚大学Gerd A. Blobel和美国费城儿童医院Peng Huang共同合作，近期取得重要工作进展，他们研究发现HIC2通过抑制BCL11A转录控制发育期血红蛋白的转换。相关研究成果2022年8月8日在线发表于《自然—遗传学》杂志上。

研究人员将HIC2鉴定为BCL11A转录的阻遏物。HIC2和BCL11A在发育过程中相互表达。成人红细胞中HIC2的强制表达抑制BCL11A转录并诱导HBG表达。HIC2与红细胞BCL11A增强子结合，以降低染色质的可及性和转录因子GATA1的结合，从而降低增强子的活性和增强子-启动子的接触。DNA结合和晶体学研究表明，直接空间位阻是HIC2在关键BCL11A增强子上抑制GATA1结合的一种机制。相反，胎儿成红细胞中HIC2的缺失会增加增强子的可及性、GATA1 结合和BCL11A的转录。HIC2通过BCL11A的发育控制成为血红蛋白转换的进化保守调节剂。

据了解，血红蛋白产生中的胎儿到成人的转换是与血红蛋白病治疗相关的发育基因控制模式。转录因子BCL11A在成年红细胞中抑制胎儿β-型珠蛋白(HBG)基因的表达主要受转录水平控制，但其潜在机制尚不清楚。

附：英文原文

Title: HIC2 controls developmental hemoglobin switching by repressing BCL11A transcription

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.

Issue&Volume: 2022-08-08

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.

DOI: 10.1038/s41588-022-01152-6

Source: https://www.nature.com/articles/s41588-022-01152-6