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SCL/TAL1-mediated transcriptional network enhances megakaryocytic specification of human embryonic stem cells.

ABSTRACT: Human embryonic stem cells (hESCs) are a unique in vitro model for studying human developmental biology and represent a potential source for cell replacement strategies. Platelets can be generated from cord blood progenitors and hESCs; however, the molecular mechanisms and determinants controlling the in vitro megakaryocytic specification of hESCs remain elusive. We have recently shown that stem cell leukemia (SCL) overexpression accelerates the emergence of hemato-endothelial progenitors from hESCs and promotes their subsequent differentiation into blood cells with higher clonogenic potential. Given that SCL participates in megakaryocytic commitment, we hypothesized that it may potentiate megakaryopoiesis from hESCs. We show that ectopic SCL expression enhances the emergence of megakaryocytic precursors, mature megakaryocytes (MKs), and platelets in vitro. SCL-overexpressing MKs and platelets respond to different activating stimuli similar to their control counterparts. Gene expression profiling of megakaryocytic precursors shows that SCL overexpression renders a megakaryopoietic molecular signature. Connectivity Map analysis reveals that trichostatin A (TSA) and suberoylanilide hydroxamic acid (SAHA), both histone deacetylase (HDAC) inhibitors, functionally mimic SCL-induced effects. Finally, we confirm that both TSA and SAHA treatment promote the emergence of CD34(+) progenitors, whereas valproic acid, another HDAC inhibitor, potentiates MK and platelet production. We demonstrate that SCL and HDAC inhibitors are megakaryopoiesis regulators in hESCs.

SUBMITTER: Toscano MG

PROVIDER: S-EPMC4426806 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature

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SCL/TAL1-mediated transcriptional network enhances megakaryocytic specification of human embryonic stem cells.

Toscano Miguel G MG Navarro-Montero Oscar O Ayllon Veronica V Ramos-Mejia Veronica V Guerrero-Carreno Xiomara X Bueno Clara C Romero Tamara T Lamolda Mar M Cobo Marien M Martin Francisco F Menendez Pablo P Real Pedro J PJ

Molecular therapy : the journal of the American Society of Gene Therapy 20141008 1

Human embryonic stem cells (hESCs) are a unique in vitro model for studying human developmental biology and represent a potential source for cell replacement strategies. Platelets can be generated from cord blood progenitors and hESCs; however, the molecular mechanisms and determinants controlling the in vitro megakaryocytic specification of hESCs remain elusive. We have recently shown that stem cell leukemia (SCL) overexpression accelerates the emergence of hemato-endothelial progenitors from h ...[more]

PMID: 25292191

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Project description:The basic-helix-loop-helix transcription factor Scl/Tal1 controls the development and subsequent differentiation of haematopoietic stem cells (HSCs). However, since few Scl target genes have been validated to date, the underlying mechanisms have remained largely unknown. Here we have employed ChIP-Seq technology to generate a genome-wide catalogue of Scl binding events in a stem/progenitor cell line followed by validation using primary fetal liver cells and comprehensive transgenic mouse assays. Transgenic analysis provided in vivo validation of multiple new direct Scl target genes and allowed us to reconstruct an in vivo validated network consisting of 17 factors and their respective regulatory elements. By coupling ChIP-Seq in model cell lines with in vivo transgenic validation and sophisticated bioinformatic analysis, we have identified a widely applicable strategy for the reconstruction of stem cell regulatory networks where biological material is otherwise limiting. Moreover, in addition to revealing multiple previously unrecognised links to known HSC regulators as well as novel links to genes not previously implicated in HSC function, comprehensive transgenic analysis of regulatory elements provided substantial new insights into the transcriptional control of several important haematopoietic regulators including Cbfa2t3h/Eto2, Cebpe, Nfe2, Zfpm1/Fog1, Erg, Mafk, Gfi1b and Myb. Keywords: Gene regulation study Examination of one transcription factor in a haematopoietic progenitor cell line The samples provided were all sourced from the same ChIP experiment. They were then split into three and sent for sequencing. The samples labelled Scl_lane7 and Scl_lane8 were sequenced in parallel using an Illumina Genome Analyzer and then aligned using Solexa alignment software. There only variation was that the Scl_lane8 sample contained twice as much of the DNA as Scl_lane7. The sample labelled Scl_vancouver was sent to an alternative site for sequencing, again on an Illumina Genome Analyzer, and was aligned using the Eland aligner software.

Dataset Information

SCL/TAL1-mediated transcriptional network enhances megakaryocytic specification of human embryonic stem cells.

Publications

SCL/TAL1-mediated transcriptional network enhances megakaryocytic specification of human embryonic stem cells.

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