Thrombopoietin signaling to chromatin elicits rapid and pervasive epigenome remodeling within poised chromatin architectures.

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Park, Hyun Jung 
Schoenfelder, Stefan 
Barozzi, Iros 
Bode, Daniel 

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 cis-regulatory responses to TPO in hematopoietic stem/progenitor cells (HSPCs) and use this paradigm of cytokine signaling to chromatin to dissect the relation between cis- regulatory activity and chromatin architecture. We show that TPO profoundly alters the transcriptome of HSPCs, with key hematopoietic regulators being transcriptionally repressed within 30 minutes of TPO. By examining cis-regulatory dynamics and chromatin architectures, we demonstrate that these changes are accompanied by rapid and extensive epigenome remodeling of cis-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 cis-regulatory dynamics and chromatin looping, we show that rapid modulation of cis-regulatory activity is largely independent of chromatin looping dynamics. Finally, we show that, although activated and repressed cis-regulatory elements share remarkably similar DNA sequence compositions, transcription factor binding patterns accurately predict rapid cis-regulatory responses to TPO.

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Genome Res
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Cold Spring Harbor Laboratory
Wellcome Trust (104710/Z/14/Z)
Medical Research Council (MC_PC_12009)
Leukaemia & Lymphoma Research (13003)
Blood Cancer UK (07037)
F.C. was supported by an EMBO long-term fellowship (1305-2015 and Marie Curie Actions LTFCOFUND2013/GA-2013-609409). Work in the Fraser lab was supported by the UK Biotechnology and Biological Sciences Research Council (grant ref. BB/J004480/1). Work in the Green laboratory was supported by Bloodwise (grant ref. 13003), the Wellcome Trust (grant ref. 104710/Z/14/Z), the Medical Research Council, the Kay Kendall Leukaemia Fund, the Cambridge NIHR Biomedical Research Center, the Cambridge Experimental Cancer Medicine Centre, the Leukemia and Lymphoma Society of America (grant ref. 07037), and a core support grant from the Wellcome Trust and MRC.