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DNA accessibility determines the level of Notch signal strength necessary for lineage specific target gene expression (Dnase-Seq)

ABSTRACT: Using the Notch signaling pathway, hematopoietic stem and progenitor cells (HSPC) sense and respond to the surrounding microenvironment to regulate cell fate outcome. Our previous studies have indicated that quantitative differences in Notch signal strength mediate cell-fate decisions during hematopoiesis. Low signal strength favors HSPC self-renewal, along with inhibition of myelopoiesis, whereas high signal strength promotes T cell differentiation. The basis for target gene selectivity in response to quantitative differences in Notch signal strength is unknown. Focusing on the high dose dependent induction of the T cell lineage, we found that targets essential for T cell commitment, including IL2ra, CD3 and Rag1, establish promoter DNA accessibility only upon exposure to high levels of Notch signaling. We further find that low promoter CpG content is a feature capable of maintaining the ground state DNA inaccessibility of these lineage determining genes. Our results suggest that DNA inaccessibility at the promoters of essential T cell commitment genes, mediated in part through low CpG content, provides robust protection against stochastic activation in inappropriate Notch signaling contexts, ensuring the maintenance of HSPC developmental plasticity.

ORGANISM(S): Mus musculus

PROVIDER: GSE142736 | GEO | 2021/03/25

REPOSITORIES: GEO

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Project description:The rapidly expanding information on the structural and functional characteristics of the human genome allows the development of genome-wide approaches to investigate the molecular circuitry wiring the genetic and epigenetic programs of clinically relevant stem/progenitor cells. Here, we define the transcriptional and epigenetic profile of human hematopoietic stem/progenitor cells (HSPC) and their committed, early myeloid and erythroid progeny. Cap Analysis of Gene Expression showed that the transcriptional state is largely maintained in the transition from early hematopoietic stem/progenitors to committed progenitor/precursors. A large fraction of differentially expressed active promoters in each cell type were classified as novel, possibly driving the expression of transcripts involved in HSPC commitment. Unannotated promoters harbored an enhancer chromatin signature, were enriched in cell-specific transcription factor binding sites, and were close to protein-coding cell-specific genes. To obtain a genome-wide description of regulatory regions, we performed ChIP-seq for histone modifications typical of promoters, enhancers and super-enhancers. ChIP-defined promoters were shared by HSPC and committed cells, whereas enhancer usage consistently changed upon commitment, thus indicating that the fine regulation of commitment is carried out by enhancer elements. The expression level of genes targeted by enhancers and super-enhancers was moderately higher in cells actively using these regulatory elements. However, functional annotation of targeted genes showed a low enrichment for cell-specific gene ontology categories. Finally, we used Moloney leukemia virus (MLV) to map functional regions of chromatin. Genomic regions targeted by MLV co-mapped with a fraction of epigenetically defined active regulatory elements, with two-third of MLV integrations falling in enhancers, and one-third in promoters. Most of MLV-targeted regulatory regions were differentially used between HSPC and their committed progeny. Analysis of the expression levels of promoters close to cell-specific MLV-targeted enhancers and functional assays indicated that MLV-defined regulatory regions are bona fide cell-specific enhancers. Finally, gene ontology analyses showed that MLV-targeted genes related to the peculiar cell identity. Overall, this study provided an overview of the differential transcriptional and epigenetic programs of HSPC and committed progenitors and represents a unique source of regulatory regions involved in HSPC commitment.

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DNA accessibility determines the level of Notch signal strength necessary for lineage specific target gene expression (Dnase-Seq)

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