Integrated genome-scale analysis of the transcriptional regulatory landscape in a blood stem/progenitor cell model

Wilson, Nicola K.; Schoenfelder, Stefan; Hannah, Rebecca; Castillo, Manuel Sánchez; Schütte, Judith; Ladopoulos, Vasileios; Mitchelmore, Joanna; Goode, Debbie K.; Calero-Nieto, Fernando J.; Moignard, Victoria; Wilkinson, Adam C.; Jimenez-Madrid, Isabel; Kinston, Sarah; Spivakov, Mikhail; Fraser, Peter; Göttgens, Berthold

doi:10.1182/blood-2015-10-677393

Cited by 52 publications

(88 citation statements)

References 60 publications

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“…2B). To more precisely localize cis-regulatory elements within DARs, we mapped active promoters and enhancers at high resolution using DNase-seq profiles in self-renewing HPC-7 cells (see Methods) (Wilson et al 2016). The vast majority (80%) of DARs encompassed elements (DHSs) from these two regulatory classes (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…To this end, we considered activated and repressed cis-regulatory elements and trained least absolute shrinkage and selection operator (lasso) logistic regression models (Tibshirani 1996) using different sets of features (Fig. 6D) and after (n = 3) 30 minutes TPO stimulation (generated as part of this study or previously published (Wilson et al 2010(Wilson et al , 2016Park et al 2015), see Supplemental Table S1), and normalized Hi-C signals as a proxy for interaction frequencies. Model performances were evaluated on a test set consisting of differentially acetylated cisregulatory elements that were not used for learning model parameters (Fig.…”

Section: Myc and Spred1mentioning

confidence: 99%

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

et al. 2018

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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 cisregulatory 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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Section: Resultsmentioning

confidence: 99%

Section: Myc and Spred1mentioning

confidence: 99%

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

et al. 2018

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“…We next turned to the association with basophil counts at 19q13 near CEBPA. As we noted above, this locus could be resolved to a single putative causal variant, rs78744187, which resides 39 kb downstream from CEBPA, near a separate +42-kb enhancer that has been shown to influence CEBPA expression along various myeloid lineages (36)(37)(38). rs78744187 appeared to be solely associated with basophil counts and showed no evidence of pleiotropic effects on other blood cell traits, including among other myeloid lineages (Dataset S4).…”

Section: Basophil Associations Illuminate Mechanisms For Hematopoieticmentioning

confidence: 95%

Comprehensive population-based genome sequencing provides insight into hematopoietic regulatory mechanisms

Guo

Nandakumar

Ulirsch

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Genetic variants affecting hematopoiesis can influence commonly measured blood cell traits. To identify factors that affect hematopoiesis, we performed association studies for blood cell traits in the population-based Estonian Biobank using highcoverage whole-genome sequencing (WGS) in 2,284 samples and SNP genotyping in an additional 14,904 samples. Using up to 7,134 samples with available phenotype data, our analyses identified 17 associations across 14 blood cell traits. Integration of WGS-based fine-mapping and complementary epigenomic datasets provided evidence for causal mechanisms at several loci, including at a previously undiscovered basophil countassociated locus near the master hematopoietic transcription factor CEBPA. The fine-mapped variant at this basophil count association near CEBPA overlapped an enhancer active in common myeloid progenitors and influenced its activity. In situ perturbation of this enhancer by CRISPR/Cas9 mutagenesis in hematopoietic stem and progenitor cells demonstrated that it is necessary for and specifically regulates CEBPA expression during basophil differentiation. We additionally identified basophil count-associated variation at another more pleiotropic myeloid enhancer near GATA2, highlighting regulatory mechanisms for ordered expression of master hematopoietic regulators during lineage specification. Our study illustrates how population-based genetic studies can provide key insights into poorly understood cell differentiation processes of considerable physiologic relevance.genome sequencing | GWAS | basophils | hematopoiesis | CEBPA

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“…on June 7, 2019. by guest www.bloodjournal.org From liver and the dorsal aorta during early fetal development. 108 At later developmental stages and in adult life, it's main function is to prime the myeloid gene expression program for neutrophilic differentiation by forming chromatin complexes, involving HSC TFs, such as PU.1, ERG, RUNX1, and C/EBPa itself to modulate CEBPA expression. In 2 separate studies, deletion of this enhancer in mice downregulated the expression of Cebpa, which ultimately reduced GMP formation and neutrophilic differentiation.…”

Section: The Topology Of the Cebpa Locus In Transcription Regulationmentioning

confidence: 99%

Expression and regulation of C/EBPα in normal myelopoiesis and in malignant transformation

Avellino

Delwel

2017

Blood

123

104

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One of the most studied transcription factors in hematopoiesis is the leucine zipper CCAAT-enhancer binding protein α (C/EBPα), which is mainly involved in cell fate decisions for myeloid differentiation. Its involvement in acute myeloid leukemia (AML) is diverse, with patients frequently exhibiting mutations, deregulation of gene expression, or alterations in the function of C/EBPα. In this review, we emphasize the importance of C/EBPα for neutrophil maturation, its role in myeloid priming of hematopoietic stem and progenitor cells, and its indispensable requirement for AML development. We discuss that mutations in the open reading frame of CEBPA lead to an altered C/EBPα function, affecting the expression of downstream genes and consequently deregulating myelopoiesis. The emerging transcriptional mechanisms of CEBPA are discussed based on recent studies. Novel insights on how these mechanisms may be deregulated by oncoproteins or mutations/variants in CEBPA enhancers are suggested in principal to reveal novel mechanisms of how CEBPA is deregulated at the transcriptional level.

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Integrated genome-scale analysis of the transcriptional regulatory landscape in a blood stem/progenitor cell model

Abstract: Key Points New genome-wide maps for 17 TFs, 3 histone modifications, DNase I sites, Hi-C, and Promoter Capture Hi-C in a stem/progenitor model. Integrated analysis shows that chromatin loops in a stem/progenitor model are characterized by specific TF occupancy patterns.

Cited by 52 publications

References 60 publications

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

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

Comprehensive population-based genome sequencing provides insight into hematopoietic regulatory mechanisms

Expression and regulation of C/EBPα in normal myelopoiesis and in malignant transformation

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