Comparative analysis of three-dimensional chromosomal architecture identifies a novel fetal hemoglobin regulatory element.
Comparative analysis of three-dimensional chromosomal architecture identifies a novel fetal hemoglobin regulatory element.
复制标题
DOI：
10.1101/gad.303461.117
复制
发表时间：
2017-08-15
影响因子：
10.5
通讯作者：
Blobel GA
中科院分区：
文献类型：
--
作者：
Huang P;Keller CA;Giardine B;Grevet JD;Davies JOJ;Hughes JR;Kurita R;Nakamura Y;Hardison RC;Blobel GA
在这项研究中，Huang等人比较了胎儿和成人成红细胞的染色体结构，发现在两个发育阶段，染色质结构和A/B区室总体上高度相似。他们的结果揭示了一个新的关键调控区域，作为血红蛋白病治疗性基因组编辑的潜在靶点，并强调了染色体构象分析在发现新的顺式控制元件方面的作用。染色质结构与转录调控紧密交织在一起。在这里，我们比较了胎儿和成人成红细胞的染色体结构，并发现，在全球范围内，染色质结构和A/B区室在两个发育阶段是高度相似的。在更精细的尺度上，我们在发育控制的β-珠蛋白基因座检测到不同的折叠模式。具体来说，在分离胎儿（γ）和成人（δ和β）珠蛋白基因（包括HBBP 1和BGLT 3非编码基因）的区域与该基因座侧翼的两个远端染色体位点（HS 5和3′ HS 1）之间发现了新的胎儿阶段特异性接触。相反，在成体细胞中，HBBP 1-BGLT 3区域接触胚胎ε-珠蛋白基因，将胎儿珠蛋白基因与增强子（基因座控制区[LCR]）物理分离。成年细胞中HBBP 1区域的缺失以更接近于胎儿细胞的方式改变接触景观，包括增加LCR-γ-珠蛋白接触。这些变化伴随着γ-珠蛋白转录的强烈增加。值得注意的是，HBBP 1去除对染色质结构和基因表达的影响与删除胎儿球蛋白阻遏物BCL 11 A的影响非常相似，这表明BCL 11 A参与了HBBP 1区域的功能。我们的研究结果揭示了一个新的关键调控区作为血红蛋白病治疗性基因组编辑的潜在靶点，并突出了染色体构象分析在发现新的顺式控制元件方面的作用。
In this study, Huang et al. compared the chromosomal architectures of fetal and adult human erythroblasts and found that, globally, chromatin structures and compartments A/B are highly similar at both developmental stages. Their results uncover a new critical regulatory region as a potential target for therapeutic genome editing for hemoglobinopathies and highlight the power of chromosome conformation analysis in discovering new cis control elements. Chromatin structure is tightly intertwined with transcription regulation. Here we compared the chromosomal architectures of fetal and adult human erythroblasts and found that, globally, chromatin structures and compartments A/B are highly similar at both developmental stages. At a finer scale, we detected distinct folding patterns at the developmentally controlled β-globin locus. Specifically, new fetal stage-specific contacts were uncovered between a region separating the fetal (γ) and adult (δ and β) globin genes (encompassing the HBBP1 and BGLT3 noncoding genes) and two distal chromosomal sites (HS5 and 3′HS1) that flank the locus. In contrast, in adult cells, the HBBP1–BGLT3 region contacts the embryonic ε-globin gene, physically separating the fetal globin genes from the enhancer (locus control region [LCR]). Deletion of the HBBP1 region in adult cells alters contact landscapes in ways more closely resembling those of fetal cells, including increased LCR–γ-globin contacts. These changes are accompanied by strong increases in γ-globin transcription. Notably, the effects of HBBP1 removal on chromatin architecture and gene expression closely mimic those of deleting the fetal globin repressor BCL11A, implicating BCL11A in the function of the HBBP1 region. Our results uncover a new critical regulatory region as a potential target for therapeutic genome editing for hemoglobinopathies and highlight the power of chromosome conformation analysis in discovering new cis control elements.
登录
查看更多内容
影响因子：
3.7
作者：
Kurita R;Suda N;Sudo K;Miharada K;Hiroyama T;Miyoshi H;Tani K;Nakamura Y
通讯作者：
Nakamura Y
影响因子：
16
作者：
Hsu SC;Gilgenast TG;Bartman CR;Edwards CR;Stonestrom AJ;Huang P;Emerson DJ;Evans P;Werner MT;Keller CA;Giardine B;Hardison RC;Raj A;Phillips-Cremins JE;Blobel GA
通讯作者：
Blobel GA
影响因子：
64.8
作者：
Dixon JR;Jung I;Selvaraj S;Shen Y;Antosiewicz-Bourget JE;Lee AY;Ye Z;Kim A;Rajagopal N;Xie W;Diao Y;Liang J;Zhao H;Lobanenkov VV;Ecker JR;Thomson JA;Ren B
通讯作者：
Ren B
影响因子：
30.8
作者：
通讯作者：
--
影响因子：
20.3
作者：
Kiefer, Christine M.;Lee, Jongjoo;Dean, Ann
通讯作者：
Dean, Ann