PT  - JOURNAL ARTICLE
AU  - Georgolopoulos, Grigorios
AU  - Iwata, Mineo
AU  - Psatha, Nikoletta
AU  - Nishida, Andrew
AU  - Som, Tannishtha
AU  - Yiangou, Minas
AU  - Stamatoyannopoulos, John A.
AU  - Vierstra, Jeff
TI  - Chromatin dynamics during hematopoiesis reveal discrete regulatory modules instructing differentiation
AID  - 10.1101/2020.04.02.022566
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.04.02.022566
4099  - http://biorxiv.org/content/early/2020/04/07/2020.04.02.022566.short
4100  - http://biorxiv.org/content/early/2020/04/07/2020.04.02.022566.full
AB  - Lineage commitment and differentiation is driven by the concerted action of master transcriptional regulators at their target chromatin sites. Multiple efforts have characterized the key transcription factors (TFs) that determine the various hematopoietic lineages. However, the temporal interactions between individual TFs and their chromatin targets during differentiation and how these interactions dictate lineage commitment remains poorly understood. We performed dense, daily, temporal profiling of chromatin accessibility (DNase I-seq) and gene expression changes (total RNA-seq) along ex vivo human erythropoiesis to comprehensively define developmentally regulated DNase I hypersensitive sites (DHSs) and transcripts. We link both distal DHSs to their target gene promoters and individual TFs to their target DHSs, revealing that the regulatory landscape is organized in distinct sequential regulatory modules that regulate lineage restriction and maturation. Finally, direct comparison of transcriptional dynamics (bulk and single-cell) and lineage potential between erythropoiesis and megakaryopoiesis illuminates the fine-scale temporal dynamics of these regulatory modules during lineage-resolution between these two fates. Collectively, these data provide novel insights into the global regulatory landscape during hematopoiesis.