Characterising open chromatin identifies novel cis-regulatory elements important for paraxial mesoderm formation and axis extension
Characterising open chromatin identifies novel cis-regulatory elements important for paraxial mesoderm formation and axis extension
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表征开放染色质识别出对轴旁中胚层形成和轴延伸重要的新型顺式调控元件
DOI：
10.1101/2020.01.20.912337
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发表时间：
2020
期刊：
影响因子：
--
通讯作者：
Mok G
中科院分区：
文献类型：
--
作者：
Mok G
多细胞生物体的发育是通过差异基因活动进行精细调控的，差异基因活动支配着细胞分化程序。然而，基因调控的时空控制的许多细节仍然知之甚少。我们使用鸡胚的可接近性来检查表征近轴中胚层沿沿着头-尾轴进行性分化的全基因组特征。近轴中胚层被组织成重复的单位，称为体节，这是分段的脊椎动物身体平面的标志。新的体节对周期性地形成轴在后端延伸。这个过程在单个胚胎内产生发育梯度，与后部体节相比，前部体节的分化更高级。体节形成后，细胞重排产生区室，包括肌肉骨骼系统的谱系，包括脊柱和肋骨的软骨，以及躯干和四肢的骨骼肌细胞。为了研究近轴中胚层如何变得区域化和图案化以最终产生这些离散的谱系，我们使用RNA-seq和ATAC-seq沿着沿着胚胎轴的时空系列研究了转录组和染色质可及性的动态变化。足迹分析揭示了已知参与轴向模式和分化的许多关键转录因子（包括HOX基因）的结合位点的差异覆盖。此外，将可接近的染色质与附近表达的基因相关联识别出候选的趋化调节元件（CRE）。作为范例，我们使用TCF 15和MEOX 1，这是至关重要的体节的形成和分化，以实验验证CREsin vivousing荧光报告。延时显微镜揭示了CRE的时空活动和突变分析揭示了必要的上游调控。MEOX 1的CRE在非洲爪蟾中是保守的并被识别。此外，人的元素是活跃的鸡。在体内表观基因组编辑TCF 15和MEOX 1克雷斯破坏基因表达调控和重演表型异常的前后轴延伸。
The development of multicellular organisms is exquisitely regulated through differential gene activity, which governs cell differentiation programs. However, many details of spatiotemporal control of gene regulation are still poorly understood. We used the accessibility of chick embryos to examine genome-wide signatures characterizing the progressive differentiation of paraxial mesoderm along the head-to-tail axis. Paraxial mesoderm becomes organized into repetitive units, termed somites, the hallmark of the segmented vertebrate body plan. New somite pairs form periodically as the axis extends at the posterior end. This process generates a developmental gradient within a single embryo, with anterior somites more advanced in their differentiation compared to posterior somites. Following somite formation, cell rearrangements generate compartments, comprising lineages of the musculoskeletal system, including cartilage of the vertebral column and ribs, and skeletal muscle cells of the trunk and limbs. To examine how paraxial mesoderm becomes regionalized and patterned to eventually generate these discrete lineages, we investigated dynamic changes of the transcriptome and of chromatin accessibility using RNA-seq and ATAC-seq across a spatiotemporal series along the embryonic axis. Footprint analysis uncovers differential coverage of binding sites for a number of key transcription factors known to be involved in axial patterning and differentiation, including HOX genes. Furthermore, associating accessible chromatin with nearby expressed genes identifies candidatecis-regulatoryelements (CRE). As exemplars we use TCF15 and MEOX1, which are crucial for somite formation and differentiation, to experimentally validate CREsin vivousing fluorescent reporters. Time-lapse microscopy reveals CRE spatiotemporal activity and mutation analysis uncovers necessary upstream regulators. The CRE for MEOX1 is conserved and recognized in Xenopus. In addition, a human element is active in chicken.In vivoepigenome editing of TCF15 and MEOX1 CREs disrupts gene expression regulation and recapitulates phenotypic abnormalities of anterior-posterior axis extension.
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影响因子：
48
作者：
Langmead, Ben;Salzberg, Steven L.
通讯作者：
Salzberg, Steven L.
影响因子：
2.5
作者：
Bothe, Ingo;Dietrich, Susanne
通讯作者：
Dietrich, Susanne
DOI：
10.1016/j.bbagrm.2014.12.008
发表时间：
2015-03-01
影响因子：
4.7
作者：
Yang, Yutao;Cui, Jiajun;Xu, Zhi-Qing David
通讯作者：
Xu, Zhi-Qing David
影响因子：
30.8
作者：
Grünewald TG;Bernard V;Gilardi-Hebenstreit P;Raynal V;Surdez D;Aynaud MM;Mirabeau O;Cidre-Aranaz F;Tirode F;Zaidi S;Perot G;Jonker AH;Lucchesi C;Le Deley MC;Oberlin O;Marec-Bérard P;Véron AS;Reynaud S;Lapouble E;Boeva V;Rio Frio T;Alonso J;Bhatia S;Pierron G;Cancel-Tassin G;Cussenot O;Cox DG;Morton LM;Machiela MJ;Chanock SJ;Charnay P;Delattre O
通讯作者：
Delattre O
在共线 Hox 基因表达的基础上：顺式特征和反式因子协调 Hox 簇激活的初始阶段。
影响因子：
2.7
作者：
R. Neijts;J. Deschamps
通讯作者：
J. Deschamps