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The promoter interactome of cardiomyocytes differentiated from human embryonic stem cells links regulatory elements to cardiac gene promoters

ABSTRACT: Long-range chromosomal interaction is an important mechanism by which differentiating cells organise three dimensional promoter-enhancer networks to regulate lineage-specifying, developmental, regulatory genes1,2. Distal promoter contacts in pluripotent stem and specialised cell types, such as foetal liver cells, form co-regulated gene networks correlated with their biological functions1. Promoter interactomes of 17 primary blood cell types also reflect high cell-type specificity3. The lineage-specifying promoter interactions can be constrained by polycomb repressive complexes and genes with specialised functions will be selectively released from this poised network during cell fate specification or differentiation2. The cis-regulatory contact upon lineage commitment is also a dynamic process that includes acquisition and loss of specific promoter interactions4. We characterise 5126 promoter-enhancer interactions specific to cardiomyocytes differentiated from human embryonic stem cells (hESC-CM) by performing a differential promoter capture Hi-C (PCHi-C)5 approach that allows physical promoter-enhancer contacts in hESC-CM to be identified against the background level of embryonic stem cells’ interactions. This approach enables us to extract key genomic regulators and their target genes highly specific to the cardiovascular development and functions.

ORGANISM(S): Homo sapiens

PROVIDER: GSE100720 | GEO | 2018/07/15

REPOSITORIES: GEO

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Project description:The realization of human embryonic stem cells (hESC) as a model for human developmental hematopoiesis and potential cell replacement strategies relies on an improved understanding of the extrinsic and intrinsic factors regulating hematopoietic-specific hESC differentiation. Mesenchymal stem cells (hMSCs) are multipotent cells of mesodermal origin that form part of hematopoietic stem cell niches and have an important role in the regulation of hematopoiesis through production of secreted factors and/or cell-to-cell interactions. We have previously shown that hESCs may be successfully maintained feeder-free using hMSC-conditioned media (MSC-CM). Here, we hypothesized that hESCs maintained in MSC-CM may be more prone to differentiation towards hematopoietic lineage than hESCs grown in standard human foreskin fibroblast (HFF)-conditioned media (HFF-CM). We report that specification into hemogenic progenitors and subsequent hematopoietic differentiation and clonogenic progenitor capacity is robustly enhanced in hESC lines maintained in MSC-CM. Interestingly, co-culture of hESCs on hMSCs fully abrogates hematopoietic specification of hESCs suggesting that the improved hematopoietic differentiation is mediated by MSC-secreted factors rather than by MSC-hESC physical interactions. To investigate the molecular mechanism involved in this process, we analyzed global (LINE-1) methylation and genome-wide promoter DNA methylation. Human ESCs grown in MSC-CM showed a decrease of 20% in global DNA methylation and a promoter DNA methylation signature consisting in 45 genes commonly hypomethylated and 102 genes frequently hypermethylated. Our data indicate that maintenance of hESCs in MSC-CM robustly augments hematopoietic specification and that the process seems mediated by MSC-secreted factors conferring a DNA methylation signature to undifferentiated hESCs which may influence further predisposition towards hematopoietic specification. Total DNA isolated by standard procedures from human embryonic stem cells (hESC) cultured in different conditioned media

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The promoter interactome of cardiomyocytes differentiated from human embryonic stem cells links regulatory elements to cardiac gene promoters

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