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Transcription factor-driven coordination of cell cycle exit and specification of cell identify during granulocytic differentiation [ChIP-Seq]

ABSTRACT: Differentiation of multipotent stem cells into mature cells is fundamental for development and homeostasis of mammalian tissues. However, how this temporal process of cell cycle exit and induction of lineage-specific transcription programs is coordinated remains largely unknown. To understand the underlying mechanisms, we investigated how the tissue-specific transcription factors CEBPA and CEBPE coordinate cell cycle exit and lineage-specification during granulocytic differentiation. We demonstrate that CEBPA promotes lineage-commitment by launching an enhancer-primed differentiation program and direct activation of CEBPE expression. Subsequently, CEBPE confers promoter-driven cell cycle exit by sequential repression of MYC target gene expression at the G1/S transition and E2F-meditated G2/M gene expression, as well as by the up-regulation of Cdk1/2/4 inhibitors. Following cell cycle exit, CEBPE unleashes the CEBPA-primed differentiation program to generate mature granulocytes. These findings highlight how tissue-specific transcription factors coordinate cell cycle exit with terminal differentiation through the use of distinct gene regulatory elements.

ORGANISM(S): Mus musculus

PROVIDER: GSE159395 | GEO | 2022/06/07

REPOSITORIES: GEO

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Transcription factor-driven coordination of cell cycle exit and specification of cell identify during granulocytic differentiation [RNA-Seq]

Project description:Differentiation of multipotent stem cells into mature cells is fundamental for development and homeostasis of mammalian tissues. However, how this temporal process of cell cycle exit and induction of lineage-specific transcription programs is coordinated remains largely unknown. To understand the underlying mechanisms, we investigated how the tissue-specific transcription factors CEBPA and CEBPE coordinate cell cycle exit and lineage-specification during granulocytic differentiation. We demonstrate that CEBPA promotes lineage-commitment by launching an enhancer-primed differentiation program and direct activation of CEBPE expression. Subsequently, CEBPE confers promoter-driven cell cycle exit by sequential repression of MYC target gene expression at the G1/S transition and E2F-meditated G2/M gene expression, as well as by the up-regulation of Cdk1/2/4 inhibitors. Following cell cycle exit, CEBPE unleashes the CEBPA-primed differentiation program to generate mature granulocytes. These findings highlight how tissue-specific transcription factors coordinate cell cycle exit with terminal differentiation through the use of distinct gene regulatory elements.

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Transcription factor-driven coordination of cell cycle exit and lineage-specification in vivo during granulocytic differentiation [ChIP-Seq_2]

Project description:Differentiation of multipotent stem cells into mature cells is fundamental for development and homeostasis of mammalian tissues, and requires the coordinated induction of lineage-specific transcriptional programs and cell cycle withdrawal. To understand the underlying regulatory mechanisms of this fundamental process, we investigated how the tissue-specific transcription factors, CEBPA and CEBPE, coordinate cell cycle exit and lineage-specification in vivo during granulocytic differentiation. We demonstrate that CEBPA promotes lineage-specification by launching an enhancer-primed differentiation program and direct activation of CEBPE expression. Subsequently, CEBPE confers promoter-driven cell cycle exit by sequential repression of MYC target gene expression at the G1/S transition and E2F-meditated G2/M gene expression, as well as by the up-regulation of Cdk1/2/4 inhibitors. Following cell cycle exit, CEBPE unleashes the CEBPA-primed differentiation program to generate mature granulocytes. These findings highlight how tissue-specific transcription factors coordinate cell cycle exit with differentiation through the use of distinct gene regulatory elements.

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CpG methylation patterns and decitabine treatment response in acute myeloid leukemia cells and normal hematopoietic precursors

Project description:The DNA hypomethylating drug decitabine maintains normal hematopoietic stem and progenitor cell (HSPC) self-renewal but induces terminal differentiation in acute myeloid leukemia (AML) cells. To better understand the basis for this contrasting treatment effect, the baseline expression of key lineage-specifying transcription factor (TF) (eg., CEBPa) and key late differentiation TF (CEBPe), was examined in normal, myelodysplastic (MDS) and AML primary cells and cell lines. To appreciate the role of differentiation in hypomethylation of some CpG by decitabine treatment but not others, promoter CpGs, analyzed by microarray and mass spectrometry, were categorized by the direction of methylation change during normal myeloid differentiation. In MDS/AML cells, high expression of CEBPa, relatively low expression of CEBPe (a gene target of CEBPa), hypermethylation of CEBPe promoter CpG, and the methylation pattern at differentiation sensitive promoter CpGs analyzed by microarray, suggested lineage-commitment and aberrant epigenetic repression of late differentiation genes. DNA hypomethylation in response to decitabine was greatest at CpGs that are hypomethylated during normal myeloid differentiation. In contrast, normal HSPC treated with decitabine retained immature morphology, and methylation significantly decreased at CpG that are hypermethylated during myeloid differentiation. Partial differentiation at baseline, and repression of key late differentiation genes by epigenetic means, likely plays a role in methylation and phenotype responses of AML cells treated with decitabine. Bisulphite converted DNA from the 208 samples were hybridised to the Illumina Cancel Panel 1 GPL9183 methylation assay

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CpG methylation patterns and decitabine treatment response in acute myeloid leukemia cells and normal hematopoietic precursors

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Next Generation Sequencing Characterization of Hematopoietic Stem and Progenitors Cells in Human Systemic Lupus Eryhtematosus

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Transcriptional heterogeneity and cell cycle regulation as a central determinant of Primitive Endoderm priming

Project description:During embryonic development cells acquire identity at the same time as they are proliferating, implying that an intrinsic facet of cell fate choice requires coupling lineage decisions to rates of cell division. How is the cell cycle regulated to promote or suppress heterogeneity and differentiation? We explore this question combining time lapse imaging with single cell RNAseq in the contexts of self-renewal, priming and differentiation of embryonic stem cells (ESCs) towards the Primitive Endoderm lineage (PrE). Since ESCs are derived from the Inner Cell Mass of the mammalian blastocyst, ESCs in standard culture conditions are transcriptionally heterogeneous containing subfractions that are primed for either of the two ICM lineages, Epiblast and PrE. These subfractions represent dynamic states that can readily interconvert in culture, and the PrE subfraction is functionally primed for endoderm differentiation. Here we find that differential regulation of cell cycle can tip the balance between these primed populations, such that naïve ESC culture conditions promote Epiblast-like expansion and PrE differentiation stimulates the selective proliferation of PrE-primed cells. In endoderm differentiation, we find that this change is accompanied by a counter-intuitive increase in G1 length that also appears replicated in vivo. While FGF/ERK signalling is a known key regulator of ESC and PrE differentiation, we find it is not just responsible for ESC heterogeneity, but also cell cycle synchronisation, required for the inheritance of similar cell cycles between sisters and cousins. Taken together, our results point to a tightly regulated relationship between transcriptional heterogeneity and cell cycle regulation in the context of lineage priming, with primed cell populations providing a pool of flexible cell types that can be expanded in a lineage specific fashion while allowing plasticity during early determination.

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Transcription factor-driven coordination of cell cycle exit and lineage-specification in vivo during granulocytic differentiation

Project description:Transcription factor-driven coordination of cell cycle exit and lineage-specification in vivo during granulocytic differentiation

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Enhancer and transcription factor dynamics within the granulocytic-monocytic lineage reveal an early differentiation block in Cebpa null progenitors

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ID1 and CEBPA coordinate epidermal progenitor cell

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