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Genome-wide analysis of GATA1, GATA2, RUNX1, FLI1 and SCL binding in primary human megakaryocytes

ABSTRACT: We have mapped the binding sites for the five key regulators GATA1, GATA2, RUNX1, FLI1 and TAL1/SCL in primary human megakaryocytes. Statistical analysis identified subsets of enriched as well as depleted combinatorial binding patterns. In particular simultaneous binding by all 5 factors was highly enriched and occurred in the vicinity of many genes known to be involved in blood and megakaryocyte development. Knock down in zebrafish of 8 of these genes with no previously known role in hematopoiesis, revealed all to be essential for thrombocyte and/or erythroid development. Combinatorial analysis of multi-factor ChIP-Seq datasets coupled with a high-throughput in vivo screen therefore offers a powerful strategy to identify novel essential regulators of complex mammalian differentiation processes.

ORGANISM(S): Homo sapiens

PROVIDER: GSE24674 | GEO | 2011/06/01

SECONDARY ACCESSION(S): PRJNA132361

REPOSITORIES: GEO

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Genome-wide analysis of GATA1, GATA2, RUNX1, FLI1 and SCL binding in primary human megakaryocytes

Project description:We have mapped the binding sites for the five key regulators GATA1, GATA2, RUNX1, FLI1 and TAL1/SCL in primary human megakaryocytes. Statistical analysis identified subsets of enriched as well as depleted combinatorial binding patterns. In particular simultaneous binding by all 5 factors was highly enriched and occurred in the vicinity of many genes known to be involved in blood and megakaryocyte development. Knock down in zebrafish of 8 of these genes with no previously known role in hematopoiesis, revealed all to be essential for thrombocyte and/or erythroid development. Combinatorial analysis of multi-factor ChIP-Seq datasets coupled with a high-throughput in vivo screen therefore offers a powerful strategy to identify novel essential regulators of complex mammalian differentiation processes. 5 transcription factors and rabbit-IgG in megakaryocytes.

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SCL knockouts in mouse megakaryocytes

Project description:The bHLH transcription factor stem cell leukemia gene (Scl) is a master regulator for hematopoiesis essential for hematopoietic specification and proper differentiation of the erythroid and megakaryocyte lineages. However, the critical downstream targets of Scl remain undefined. Here, we identified a novel Scl target gene, transcription factor myocyte enhancer factor 2 C (Mef2C) from Sclfl/fl fetal liver progenitor cell lines. Analysis of Mef2C-/- embryos showed that Mef2C, in contrast to Scl, is not essential for specification into primitive or definitive hematopoietic lineages. However, adult VavCre+Mef2Cfl/fl mice exhibited platelet defects similar to those observed in Scl deficient mice. The platelet counts were reduced, while platelet size was increased and the platelet shape and granularity was altered. Furthermore, megakaryopoiesis was severely impaired in vitro. ChIP-on-chip analysis revealed that Mef2C is directly regulated by Scl in megakaryocytic cells, but not in erythroid cells. In addition, an Scl independent requirement for Mef2C in B-lymphoid homeostasis was observed in Mef2C-deficient mice, characterized as severe age-dependent reduction of specific B cell progenitor populations reminiscent of premature aging. In summary, this work identifies Mef2C as an integral member of hematopoietic transcription factors with distinct upstream regulatory mechanisms and functional requirements in megakaryocyte and B-lymphoid lineages.

2009-01-31 | GSE14478 | GEO

Scl specifies hemogenic endothelium and inhibits cardiogenesis via primed enhancers [RRBS]

Project description:Scl/Tal1 confers hemogenic competence and prevents cardiomyogenesis in embryonic endothelium. Here we show that Scl both directly activates a broad gene regulatory network required for hematopoietic stem/progenitor cell (HS/PC) development, and represses transcriptional regulators required for cardiogenesis. Cardiac repression occurs during a short developmental window through Scl binding to distant cardiac enhancers that harbor H3K4me1 at this stage. Scl binding to hematopoietic regulators extends throughout HS/PC and erythroid development and spreads from distant enhancers to promoters. Surprisingly, Scl complex partners Gata 1 and 2 are dispensable for hematopoietic versus cardiac specification and Scl binding to the majority of its target genes. Nevertheless, Gata factors co-operate with Scl to activate selected transcription factors to facilitate HS/PC emergence from hemogenic endothelium. These results uncover a dual function for Scl in dictating hematopoietic versus cardiac fate choice and suggest a mechanism by which lineage-specific bHLH factors direct the divergence of competing fates.

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Scl specifies hemogenic endothelium and inhibits cardiogenesis via primed enhancers [expression]

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