Spatial regulation by multiple Gremlin1 enhancers provides digit development with cis-regulatory robustness and evolutionary plasticity.
Spatial regulation by multiple Gremlin1 enhancers provides digit development with cis-regulatory robustness and evolutionary plasticity.
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DOI：
10.1038/s41467-021-25810-1
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发表时间：
2021-09-21
影响因子：
16.6
通讯作者：
Zeller R
中科院分区：
文献类型：
--
作者：
Malkmus J;Ramos Martins L;Jhanwar S;Kircher B;Palacio V;Sheth R;Leal F;Duchesne A;Lopez-Rios J;Peterson KA;Reinhardt R;Onimaru K;Cohn MJ;Zuniga A;Zeller R
精确的顺式调控基因表达对正常胚胎发生和组织发育至关重要。BMP拮抗剂Gremlin1 （Grem1）是协调控制肢体芽发育的信号系统中的关键节点。在这里，我们使用小鼠反向遗传学来鉴定Grem1基因组景观中的增强子，以及在肢体芽发育过程中协调Grem1时空表达动态的潜在顺式调控逻辑。我们确定转录水平以加性方式控制，而空间调节需要多个增强子之间的协同相互作用。破坏这些相互作用表明，改变空间调节而不是降低Grem1转录物水平预示着手指融合和丢失。其中两种增强子是进化古老的，从基础鱼类到哺乳动物都高度保守。通过对不同物种中这些增强子的分析，揭示了四足动物和基底鱼类中Grem1调控的空间可塑性，为研究五足动物肢体从鳍到肢的转变和进化多样化提供了新的思路。BMP拮抗剂Gremlin1平衡BMP和SHH信号，使肢体芽发育具有稳健性。在这里，作者确定了以一种加性的方式控制Grem1水平的增强子，并以协同的方式进行空间调控，为数字模式提供顺式调控稳健性和进化可塑性。
Precise cis-regulatory control of gene expression is essential for normal embryogenesis and tissue development. The BMP antagonist Gremlin1 (Grem1) is a key node in the signalling system that coordinately controls limb bud development. Here, we use mouse reverse genetics to identify the enhancers in the Grem1 genomic landscape and the underlying cis-regulatory logics that orchestrate the spatio-temporal Grem1 expression dynamics during limb bud development. We establish that transcript levels are controlled in an additive manner while spatial regulation requires synergistic interactions among multiple enhancers. Disrupting these interactions shows that altered spatial regulation rather than reduced Grem1 transcript levels prefigures digit fusions and loss. Two of the enhancers are evolutionary ancient and highly conserved from basal fishes to mammals. Analysing these enhancers from different species reveal the substantial spatial plasticity in Grem1 regulation in tetrapods and basal fishes, which provides insights into the fin-to-limb transition and evolutionary diversification of pentadactyl limbs. The BMP antagonist Gremlin1 balances BMP and SHH signalling, endowing limb bud development with robustness. Here, the authors identify enhancers controlling Grem1 levels in an additive, and spatial regulation in a synergistic manner, providing digit patterning with cis-regulatory robustness and evolutionary plasticity.
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影响因子：
10.7
作者：
Castresana, J
通讯作者：
Castresana, J
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
64.5
作者：
Long, Hannah K.;Prescott, Sara L.;Wysocka, Joanna
通讯作者：
Wysocka, Joanna
影响因子：
16.6
作者：
Hörnblad A;Bastide S;Langenfeld K;Langa F;Spitz F
通讯作者：
Spitz F
影响因子：
11.8
作者：
Lopez-Rios, Javier;Speziale, Dario;Robay, Dimitri;Scotti, Martina;Osterwalder, Marco;Nusspaumer, Gretel;Galli, Antonella;Hollaender, Georg A.;Kmita, Marie;Zeller, Rolf
通讯作者：
Zeller, Rolf