title: Active enhancers are delineated de novo during hematopoiesis, with limited lineage fidelity among specified primary blood cells.
abstract: Tissues may adopt diverse strategies to establish specific transcriptional programs in daughter lineages. In intestinal crypts, enhancers for genes expressed in both major cell types appear broadly permissive in stem and specified progenitor cells. In blood, another self-renewing tissue, it is unclear when chromatin becomes permissive for transcription of genes expressed in distinct terminal lineages. Using chromatin immunoprecipitation (ChIP) combined with deep sequencing (ChIP-seq) to profile activating histone marks, we studied enhancer dynamics in primary mouse blood stem, progenitor, and specified cells. Stem and multipotent progenitor cells show scant H3K4me2 marking at enhancers bound by specific transcription factors in their committed progeny. Rather, enhancers are modulated dynamically and serially, with substantial loss and gain of H3K4me2, at each cellular transition. Quantitative analysis of these dynamics accurately modeled hematopoiesis according to Waddington's notion of epigenotypes. Delineation of enhancers in terminal blood lineages coincides with cell specification, and enhancers active in single lineages show well-positioned H3K4me2- and H3K27ac-marked nucleosomes and DNaseI hypersensitivity in other cell types, revealing limited lineage fidelity. These findings demonstrate that enhancer chronology in blood cells differs markedly from that in intestinal crypts. Chromatin dynamics in hematopoiesis provide a useful foundation to consider classical observations such as cellular reprogramming and multilineage locus priming.
authors.affiliation: Department of Medical Oncology, Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA;
authors.forename: Annouck
authors.initials: A
authors.lastname: Luyten
authors.affiliation: Department of Biostatistics and Computational Biology, Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Harvard School of Public Health, Boston, Massachusetts 02215, USA;
authors.forename: Chongzhi
authors.initials: C
authors.lastname: Zang
authors.affiliation: Department of Biostatistics and Computational Biology, Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Harvard School of Public Health, Boston, Massachusetts 02215, USA; ramesh_shivdasani@dfci.harvard.edu xsliu@jimmy.harvard.edu.
authors.forename: X Shirley
authors.initials: XS
authors.lastname: Liu
authors.affiliation: Department of Medical Oncology, Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA; Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA; Harvard Stem Cell Institute, Cambridge, Massachusetts 02138, USA ramesh_shivdasani@dfci.harvard.edu xsliu@jimmy.harvard.edu.
authors.forename: Ramesh A
authors.initials: RA
authors.lastname: Shivdasani
mesh_terms: D000818:Animals; D001773:Blood Cells / Q000166:cytology* / Q000378:metabolism*; D002454:Cell Differentiation; D019070:Cell Lineage; D004742:Enhancer Elements, Genetic / Q000235:genetics*; D044127:Epigenesis, Genetic; D006410:Hematopoiesis / Q000235:genetics*; D006657:Histones / Q000378:metabolism; D051379:Mice; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism
chemical_list: D006657:Histones
keywords: chromatin dynamics; hematopoiesis; nucleosome dynamics; tissue differentiation; tissue-selective enhancers