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

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

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 characterised by specific TF occupancy patterns.

Abstract

Comprehensive study of transcriptional control processes will be required to enhance our understanding of both normal and malignant haematopoiesis. Modern sequencing technologies have revolutionized our ability to generate genome-scale expression and histone modification profiles, transcription factor binding maps and also comprehensive chromatin looping information. Many of these technologies however require large numbers of cells, and therefore cannot be applied to rare haematopoietic stem/progenitor cell (HSPC) populations. The stem cell factor (SCF) dependent multipotent progenitor cell line HPC-7 represents a well recognised cell line model for HSPCs. Here we report genome-wide maps for 17 transcription factors (TFs), 3 histone modifications, DNase I hypersensitive sites and high-resolution promoter-enhancer interactomes in HPC-7 cells. Integrated analysis of these complementary datasets revealed transcription factor occupancy patterns of genomic regions involved in promoter-anchored loops. Moreover, preferential associations between pairs of transcription factors bound at either ends of chromatin loops lead to the identification of four previously unrecognised protein-protein interactions between key blood stem cell regulators. All HPC-7 genome-scale datasets are freely available both through standard repositories and a user-friendly web interface. Together with previously generated genome-scale datasets, this study integrates HPC-7 data into a genomic resource on a par with ENCODE tier 1 cell lines, and importantly the only current model with comprehensive genome-scale data that is relevant to HSPC biology.

  • Submitted October 22, 2015.
  • Accepted January 7, 2016.