title: Dynamic Gene Regulatory Networks of Human Myeloid Differentiation.
abstract: The reconstruction of gene regulatory networks underlying cell differentiation from high-throughput gene expression and chromatin data remains a challenge. Here, we derive dynamic gene regulatory networks for human myeloid differentiation using a 5-day time series of RNA-seq and ATAC-seq data. We profile HL-60 promyelocytes differentiating into macrophages, neutrophils, monocytes, and monocyte-derived macrophages. We find a rapid response in the expression of key transcription factors and lineage markers that only regulate a subset of their targets at a given time, which is followed by chromatin accessibility changes that occur later along with further gene expression changes. We observe differences between promyelocyte- and monocyte-derived macrophages at both the transcriptional and chromatin landscape level, despite using the same differentiation stimulus, which suggest that the path taken by cells in the differentiation landscape defines their end cell state. More generally, our approach of combining neighboring time points and replicates to achieve greater sequencing depth can efficiently infer footprint-based regulatory networks from long series data.
authors.affiliation: Developmental and Cell Biology, University of California Irvine, Irvine, CA 92697-2300, USA; Center for Complex Biological Systems, University of California Irvine, Irvine, CA 92697-2300, USA.
authors.forename: Ricardo N
authors.initials: RN
authors.lastname: Ramirez
authors.affiliation: Developmental and Cell Biology, University of California Irvine, Irvine, CA 92697-2300, USA; Center for Complex Biological Systems, University of California Irvine, Irvine, CA 92697-2300, USA.
authors.forename: Nicole C
authors.initials: NC
authors.lastname: El-Ali
authors.affiliation: Developmental and Cell Biology, University of California Irvine, Irvine, CA 92697-2300, USA; Center for Complex Biological Systems, University of California Irvine, Irvine, CA 92697-2300, USA.
authors.forename: Mikayla Anne
authors.initials: MA
authors.lastname: Mager
authors.affiliation: Center for Complex Biological Systems, University of California Irvine, Irvine, CA 92697-2300, USA.
authors.forename: Dana
authors.initials: D
authors.lastname: Wyman
authors.affiliation: Centro de Investigacion Principe Felipe, 46012 Valencia, Spain; Microbiology and Cell Science, University of Florida, Gainesville, FL 32603, USA.
authors.forename: Ana
authors.initials: A
authors.lastname: Conesa
authors.affiliation: Developmental and Cell Biology, University of California Irvine, Irvine, CA 92697-2300, USA; Center for Complex Biological Systems, University of California Irvine, Irvine, CA 92697-2300, USA. Electronic address: ali.mortazavi@uci.edu.
authors.forename: Ali
authors.initials: A
authors.lastname: Mortazavi
mesh_terms: D015415:Biomarkers / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics*; D002460:Cell Line; D019070:Cell Lineage; D053263:Gene Regulatory Networks; D006801:Humans; D008957:Models, Genetic; D022423:Myeloid Cells / Q000166:cytology* / Q000378:metabolism
chemical_list: D015415:Biomarkers
keywords: ATAC-seq; RNA-seq; footprinting; gene regulatory network; macrophage; monocyte; myeloid differentiation; neutrophil; open chromatin