Unknown,Transcriptomics,Genomics,Proteomics

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Cell cycle analysis of histone marks and 4C in human Fucci ESCs

ABSTRACT: Using the Fucci cell cycle indicator system in hESCs, we evaluated the patterns of bivalent histone marks and enhancer histone marks during the cell cycle by ChIP-seq. We further evaluated how the chromatin architecture changed during the cell cycle. We found that bivalent domains are cell cycle regulated, and H3K4me3 specifically peaks during the late G1 stage of the cell cycle. H3K27me3, however, is largely unchanged during the cell cycle. Cell cycle-regulated bivalent domains interact with enhancers and form cell cycle regulated chromatin interactions. FACS-isolated cell cycle fractions (DN, early G1; KO2, late G1; AzL, S-phase; and AzH, G2/M) from Fucci hESCs were subject to ChIP-seq for H3K4me3, H3K27me3, H3K27ac and H3K4me1, and used for sequencing along with input controls for each of the 4 cell cycle fractions (20 samples total), using Illumina platform, or 4C-seq for each cell cycle fraction using viewpoints neighboring the GATA6 or SOX17 promoters.

ORGANISM(S): Homo sapiens

SUBMITTER: Stephen Dalton

PROVIDER: E-GEOD-61176 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Formation and maturation of a functional blood vascular system is required for the development and maintenance of all tissues in the body. During the process of blood vessel development, primordial endothelial cells are formed and become specified toward arterial or venous fates to generate a circulatory network that provides nutrients and oxygen to, and removes metabolic waste from, all tissues. Specification of arterial and venous endothelial cells occurs in conjunction with suppression of endothelial cell cycle progression, and endothelial cell hyperproliferation is associated with potentially lethal arterial-venous malformations. However, the mechanistic role that cell cycle state plays in arterial-venous specification is unknown. Herein, studying vascular development in Cdh5-CreERT2;R26FUCCI2aR reporter mice, we find that venous and arterial endothelial cells exhibit a propensity for different cell cycle states during development and in adulthood. That is, venous endothelial cells are predominantly FUCCI-Negative, while arterial endothelial cells are enriched for the FUCCI-Red reporter. Single cell RNA sequencing analysis of developing retinal endothelial cells reveals that venous endothelial cells are enriched for the FUCCI-Negative state and BMP signaling, while arterial endothelial cells are enriched for the FUCCI-Red state and TGF-b signaling. Further transcriptional analyses and live imaging of cultured endothelial cells expressing the FUCCI reporter show that reporter-negative corresponds to an early G1 state and reporter-red corresponds to late G1 state. We find the early G1 state is essential for BMP4-induced venous gene expression, whereas late G1 state is essential for TGF-b1-induced arterial gene expression. In a mouse model of endothelial cell hyperproliferation and disrupted arterial-venous specification, pharmacological inhibition of endothelial cell cycle prevents the vascular defects. Collectively, our results show that endothelial cell cycle control plays a key role in arterial-venous network formation, and distinct cell cycle states provide distinct windows of opportunity for the molecular induction of arterial vs. venous specification.

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Cell cycle analysis of histone marks and 4C in human Fucci ESCs

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