Cambridge Institute for Medical Research, Medical Research Council/Wellcome Trust Stem Cell Institute, and Department of Haematology, University of Cambridge, Cambridge CB2 0XY, United Kingdom.
Nuclear Dynamics Programme, The Babraham Institute, Cambridge CB22 3AT, United Kingdom.
Genome Res. 2018 Mar 1;28(3):295-309. doi: 10.1101/gr.227272.117.
Thrombopoietin (TPO) is a critical cytokine regulating hematopoietic stem cell maintenance and differentiation into the megakaryocytic lineage. However, the transcriptional and chromatin dynamics elicited by TPO signaling are poorly understood. Here, we study the immediate early transcriptional and -regulatory responses to TPO in hematopoietic stem/progenitor cells (HSPCs) and use this paradigm of cytokine signaling to chromatin to dissect the relationship between -regulatory activity and chromatin architecture. We show that TPO profoundly alters the transcriptome of HSPCs, with key hematopoietic regulators being transcriptionally repressed within 30 min of TPO. By examining -regulatory dynamics and chromatin architectures, we demonstrate that these changes are accompanied by rapid and extensive epigenome remodeling of -regulatory landscapes that is spatially coordinated within topologically associating domains (TADs). Moreover, TPO-responsive enhancers are spatially clustered and engage in preferential homotypic intra- and inter-TAD interactions that are largely refractory to TPO signaling. By further examining the link between -regulatory dynamics and chromatin looping, we show that rapid modulation of -regulatory activity is largely independent of chromatin looping dynamics. Finally, we show that, although activated and repressed -regulatory elements share remarkably similar DNA sequence compositions, transcription factor binding patterns accurately predict rapid -regulatory responses to TPO.
血小板生成素 (TPO) 是一种关键的细胞因子，调节造血干细胞的维持和向巨核细胞谱系的分化。然而，TPO 信号引发的转录和染色质动力学仍知之甚少。在这里，我们研究了造血干细胞/祖细胞 (HSPC) 中 TPO 信号的即刻早期转录和调控反应，并利用这种细胞因子信号转导到染色质的范例来剖析调控活性和染色质结构之间的关系。我们表明，TPO 深刻地改变了 HSPC 的转录组，关键的造血调节因子在 TPO 作用 30 分钟内被转录抑制。通过检查调控动态和染色质结构，我们证明这些变化伴随着调控景观的快速和广泛的表观基因组重塑，这在拓扑关联域 (TAD) 内是空间协调的。此外，TPO 反应性增强子在空间上聚集，并进行优先的同型内和跨 TAD 相互作用，这些作用在很大程度上对 TPO 信号不敏感。通过进一步研究调控动态和染色质环之间的联系，我们表明，调控活性的快速调节在很大程度上独立于染色质环动力学。最后，我们表明，尽管激活和抑制的调控元件具有惊人相似的 DNA 序列组成，但转录因子结合模式可准确预测 TPO 对快速调控反应的影响。
