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Regeneration and how blood vessels are built

Knowing how human blood vessels are constructed is desperately needed to advance regenerative medicine. Collaborative research is helping identify the histone code which affects how a gene is read/transcribed, and the changes that occur over time as stem cells differentiate into blood vessels. One blood vessel group (ETS/GATA/SOX) has a previously unknown role.


Regenerative medicine has made remarkable progress due to research with embryonic stem (ES) cells and induced pluripotent stem (iPS) cells. However, the mechanism of how blood vessels are constructed from these undifferentiated cells is not yet very clear. During the creation of new blood vessels, the vascular endothelial growth factor (VEGF) protein differentiates stem cells into vascular endothelial cells and stimulates them to create new blood vessels. Researchers at Kumamoto University added VEGF to undifferentiated ES cells and tracked the behavior of the entire genome and epigenome changes over time in vitro.

Collaborations between Kumamoto University, Kyoto University, and the University of Tokyo in Japan investigated changes in gene functions that occur when stem cells become vascular cells, and made a surprising discovery. Using embryonic stem (ES) cells developed at the Center for iPS Cell Research and Application (CiRA) in Kyoto University, researchers collected RNA and histones of each cell immediately after VEGF stimulation (0 hour), before differentiation (6 hours), during differentiation (12 - 24 hours), and after differentiation (48 hours). They then analyzed these changes in the whole genome and epigenome using next generation deep sequencing.

In the process of blood vessel differentiation, function of the protein ETS variant 2 (ETV2) which determines the differentiation into vascular endothelium was first induced within 6 hours of differentiation stimulation. The protein GATA2 which binds to ETV2 and supports vascular endothelial differentiation was induced immediately thereafter. Transcription factors SOX and FLI1, both important for endothelial differentiation were induced between 12 and 24 hours. After 48 hours, a system of transcription was established in which genes unique to vascular endothelial differentiation were induced.


Examination of the histone code revealed that regulatory regions of the genes for transcription factors (ETS/GATA/SOX) gradually switched from a "brake" on the histone mark which suppresses transcription/reading of the gene, to "accelerate" the histone mark which activates transcription/reading and differentiation into vascular endothelial cells.

Previously, it was believed this region of bivalent modifications of histones with instructions to "accelerate" or "brake" histones coexisted to control differentiation from ES cells to specific cell types, perhaps in a pulsing motion and not the gradual motion over time discovered.

When transcription factors lose their function, differentiation into vascular endothelial cells is completely suppressed/stopped. Collectively, the transcription factors (ETS/GATA/SOX) not only induce vascular endothelial differentiation, but also suppress regression into an undifferentiated state and differentiation into other ectodermal or endoderm-derived cells.

Knowing the functions of these transcription factors, combined with new gene editing techniques such as CRISPR-Cas9, will allow for a more efficient regeneration of blood vessels.

This finding was first reported in "Nucleic Acid Research" on March 17th, 2017.

Abstract
Although studies of the differentiation from mouse embryonic stem (ES) cells to vascular endothelial cells (ECs) provide an excellent model for investigating the molecular mechanisms underlying vascular development, temporal dynamics of gene expression and chromatin modifications have not been well studied. Herein, using transcriptomic and epigenomic analyses based on H3K4me3 and H3K27me3 modifications at a genome-wide scale, we analysed the EC differentiation steps from ES cells and crucial epigenetic modifications unique to ECs. We determined that Gata2, Fli1, Sox7 and Sox18 are master regulators of EC that are induced following expression of the haemangioblast commitment pioneer factor, Etv2. These master regulator gene loci were repressed by H3K27me3 throughout the mesoderm period but rapidly transitioned to histone modification switching from H3K27me3 to H3K4me3 after treatment with vascular endothelial growth factor. SiRNA knockdown experiments indicated that these regulators are indispensable not only for proper EC differentiation but also for blocking the commitment to other closely aligned lineages. Collectively, our detailed epigenetic analysis may provide an advanced model for understanding temporal regulation of chromatin signatures and resulting gene expression profiles during EC commitment. These studies may inform the future development of methods to stimulate the vascular endothelium for regenerative medicine.

Key word search: vascular endothelial growth factor a electroconvulsive therapy gene expression mesoderm endothelial cells vascular endothelium chromatin embryo gene expression profiling genes genes, regulator genome heat (physical force) histones mice transcription factor rna, small interfering epigenetics hemangioblasts epidural cortical stimulation regenerative medicine gata2 gene fli1 gene


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May 25, 2017   Fetal Timeline   Maternal Timeline   News   News Archive   



This study identifies how histones allow for the transcription (or reading) of genes. Not through a series of "stop/go" signals or "pulses" as previously thought, but as a continuous wave building to a crescendo
overtime as it converts stem cells into blood vessel cells. This timing is an important consideration
in designing regenerative therapy experiments.
Image Credit: Public domain

 


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