title: Dynamic shifts in occupancy by TAL1 are guided by GATA factors and drive large-scale reprogramming of gene expression during hematopoiesis.
abstract: We used mouse ENCODE data along with complementary data from other laboratories to study the dynamics of occupancy and the role in gene regulation of the transcription factor TAL1, a critical regulator of hematopoiesis, at multiple stages of hematopoietic differentiation. We combined ChIP-seq and RNA-seq data in six mouse cell types representing a progression from multilineage precursors to differentiated erythroblasts and megakaryocytes. We found that sites of occupancy shift dramatically during commitment to the erythroid lineage, vary further during terminal maturation, and are strongly associated with changes in gene expression. In multilineage progenitors, the likely target genes are enriched for hematopoietic growth and functions associated with the mature cells of specific daughter lineages (such as megakaryocytes). In contrast, target genes in erythroblasts are specifically enriched for red cell functions. Furthermore, shifts in TAL1 occupancy during erythroid differentiation are associated with gene repression (dissociation) and induction (co-occupancy with GATA1). Based on both enrichment for transcription factor binding site motifs and co-occupancy determined by ChIP-seq, recruitment by GATA transcription factors appears to be a stronger determinant of TAL1 binding to chromatin than the canonical E-box binding site motif. Studies of additional proteins lead to the model that TAL1 regulates expression after being directed to a distinct subset of genomic binding sites in each cell type via its association with different complexes containing master regulators such as GATA2, ERG, and RUNX1 in multilineage cells and the lineage-specific master regulator GATA1 in erythroblasts.
authors.affiliation: Center for Comparative Genomics and Bioinformatics, Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, Pennsylvania 16802, USA;
authors.forename: Weisheng
authors.initials: W
authors.lastname: Wu
authors.affiliation: Center for Comparative Genomics and Bioinformatics, Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, Pennsylvania 16802, USA;
authors.forename: Christapher S
authors.initials: CS
authors.lastname: Morrissey
authors.affiliation: Center for Comparative Genomics and Bioinformatics, Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, Pennsylvania 16802, USA;
authors.forename: Cheryl A
authors.initials: CA
authors.lastname: Keller
authors.affiliation: Center for Comparative Genomics and Bioinformatics, Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, Pennsylvania 16802, USA;
authors.forename: Tejaswini
authors.initials: T
authors.lastname: Mishra
authors.affiliation: Division of Hematology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA;
authors.forename: Maxim
authors.initials: M
authors.lastname: Pimkin
authors.affiliation: Division of Hematology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA; Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Gerd A
authors.initials: GA
authors.lastname: Blobel
authors.affiliation: Division of Hematology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA; Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Mitchell J
authors.initials: MJ
authors.lastname: Weiss
authors.affiliation: Center for Comparative Genomics and Bioinformatics, Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, Pennsylvania 16802, USA;
authors.forename: Ross C
authors.identifier: http://orcid.org/0000-0003-4084-7516
authors.initials: RC
authors.lastname: Hardison
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D001665:Binding Sites; D002454:Cell Differentiation / Q000235:genetics; D002843:Chromatin / Q000235:genetics / Q000378:metabolism; D047369:Chromatin Immunoprecipitation; D016000:Cluster Analysis; D019295:Computational Biology; D066264:Datasets as Topic; D041905:Erythroid Cells / Q000166:cytology / Q000378:metabolism; D050980:GATA Transcription Factors / Q000378:metabolism*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006410:Hematopoiesis; D059014:High-Throughput Nucleotide Sequencing; D006657:Histones / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D058977:Molecular Sequence Annotation; D059372:Nucleotide Motifs; D056510:Position-Specific Scoring Matrices; D011485:Protein Binding; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1; D059467:Transcriptome
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D002843:Chromatin; D050980:GATA Transcription Factors; D006657:Histones; D011518:Proto-Oncogene Proteins; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1; C489366:Tal1 protein, mouse