小柯机器人

美国圣犹大儿童研究医院Mitchell J. Weiss课题组发现，GATA1和NF-Y在遗传性持续性胎儿血红蛋白中对γ-球蛋白基因表达具有激活作用。2021年8月2日，国际知名学术期刊《自然—遗传学》在线发表了这一成果。

研究人员表示，胎儿血红蛋白的遗传性持续存在（HPFH）通过抑制γ-血红蛋白（HBG1/HBG2）到β-血红蛋白（HBB）基因表达的发育转换改善了β-血红蛋白病症。某些形式的HPFH与γ-球蛋白启动子变体有关，这些变体要么破坏了转录抑制因子的结合基序，要么为转录激活因子创造了新的基序。这些变体如何在产后维持γ-球蛋白基因的表达仍未确定。

研究人员在携带不同HPFH变体的红细胞中绘制了γ-球蛋白启动子序列的功能图。那些破坏BCL11A抑制器结合元件的启动子，通过促进核转录因子Y（NF-Y）招募到附近的近端CCAAT框和GATA1招募到上游模体，从而诱导γ-球蛋白的表达。近端CCAAT元件对HPFH变体来说变得可有可无，因为它为激活因子NF-Y或KLF1产生了新的结合模体，但GATA1的招募仍然是至关重要的。这些研究结果确定了转录因子及其顺式调控元件在不同形式的HPFH中激活γ-球蛋白表达的不同机制，其中一些机制正在通过治疗性基因组编辑重新创建。

附：英文原文

Title: Activation of γ-globin gene expression by GATA1 and NF-Y in hereditary persistence of fetal hemoglobin

Author: Doerfler, Phillip A., Feng, Ruopeng, Li, Yichao, Palmer, Lance E., Porter, Shaina N., Bell, Henry W., Crossley, Merlin, Pruett-Miller, Shondra M., Cheng, Yong, Weiss, Mitchell J.

Issue&Volume: 2021-08-02

Abstract: Hereditary persistence of fetal hemoglobin (HPFH) ameliorates β-hemoglobinopathies by inhibiting the developmental switch from γ-globin (HBG1/HBG2) to β-globin (HBB) gene expression. Some forms of HPFH are associated with γ-globin promoter variants that either disrupt binding motifs for transcriptional repressors or create new motifs for transcriptional activators. How these variants sustain γ-globin gene expression postnatally remains undefined. We mapped γ-globin promoter sequences functionally in erythroid cells harboring different HPFH variants. Those that disrupt a BCL11A repressor binding element induce γ-globin expression by facilitating the recruitment of nuclear transcription factor Y (NF-Y) to a nearby proximal CCAAT box and GATA1 to an upstream motif. The proximal CCAAT element becomes dispensable for HPFH variants that generate new binding motifs for activators NF-Y or KLF1, but GATA1 recruitment remains essential. Our findings define distinct mechanisms through which transcription factors and their cis-regulatory elements activate γ-globin expression in different forms of HPFH, some of which are being recreated by therapeutic genome editing.

DOI: 10.1038/s41588-021-00904-0

Source: https://www.nature.com/articles/s41588-021-00904-0

Nature Genetics：《自然—遗传学》，创刊于1992年。隶属于施普林格·自然出版集团，最新IF：41.307
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