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First Epigenetic Database for Normal Endothelial Cells Reveals a Unique “Switch” for Blood Vessel Generation
These findings are expected to advance research in endothelial activation and angiogenesis and facilitate selective epigenomic drug discovery for age-related vascular diseases.

Professor Takashi Minami at Kumamoto University and colleagues at universities in Japan have discovered a unique epigenetic modification that is specific to key transcriptional factors that trigger the expression of angiogenesis-related genes. By systematically analysing epigenetic changes in angiogenesis-stimulated vascular endothelial cells, their study has also demonstrated that the histone modifiers responsible for this alteration – a bivalent histone-mark switch – are critical for postnatal angiogenesis.

Extending throughout the body, the vascular system is a critical infrastructure that transports oxygen and various nutrients for biological homeostasis. To maintain health, endothelial cells, which form the basis of blood vessels, need to function properly. Dysfunctional endothelial cells could lead to the overactivation or misplaced activation of the vascular system, which could cause cancer, cerebrovascular disease, or heart disease. Despite its importance, scientists have yet to fully understand the epigenome dynamics of vascular endothelial cells. In particular, the precise mechanisms by which endothelial cells mediate postnatal angiogenesis and epigenomic changes have remained elusive.

To fill this gap, Dr. Minami and his team performed a genome-wide analysis of epigenetic changes in vascular endothelial growth factor (VEGF), which is essential for angiogenesis. Taking into account mRNAs and histone modification changes, the researchers tracked VEGF signalling over a minute-by-minute basis. The scientists subsequently catalogued and mapped these changes to locate where these modifications occurred. They also used a mouse model to determine whether the histone-mark changes from their comprehensive database are critical for postnatal angiogenesis.

Their investigation revealed that when vascular endothelial cells receive VEGF signalling, a unique “bivalent histone switch” is triggered. This modification is limited to immediate-early type transcription factors essential for angiogenesis. They also found that this “bivalent histone switch” activation coincided with the timing of the transfer of nuclear factor of activated T-cells (NFAT) into the nucleus. NFAT are transcription factors that are important in immune response and cardiac muscle development.

This histone switch is referred to as “bivalent” because both the transcriptional brake H3K27me3 and transcriptional accelerator H3K4me3, which mark epigenetic histone modifications, coexist in the region where transcription factors are expressed. While scientists have found that H3K27me3 and H3K4me3 occur in the regulatory region of transcription factor expression during the differentiation of embryonic stem cells and induced pluripotent stem cells, the bivalent switch in endothelial cells, by contrast, is highly dynamic and specific. In endothelial cells, the switch occurs in the gene region of a group of angiogenesis-inducing/-essential transcription factors that are fully enriched in H3K27me3 brake marks.

Additionally, the researchers examined the activity of the polycomb repressive complex (PRC), which maintains gene transcriptional repression by catalysing the methylation of histone, thereby regulating cellular identity and normal organismal development. Their studies revealed that the “non-canonical” or “variant” PRC1.3 was bound to this genomic region 15 minutes after VEGF stimulation and disabled the brakes until the canonical PRC1-brake returned to the endothelium at 60 minutes.

Importantly, 15 minutes after treating the endothelial cells with VEGF, and during the same time as NFAT nuclear localisation, NFAT was observed to interact with PTIP-triggered H3K4me3 markers at the region of immediate-early type transcription factors. This resulted in an angiogenesis-specific bivalent switch. PTIP is a component (guidance factor) of the MLL3/4, H3K4me3 marking enzyme. To determine the exact role of PRC and PTIP in angiogenesis, the researchers removed PRC1.3 and PTIP specifically from endothelial cells. Their experiment revealed that the removal of PRC1.3 and PTIP suppressed only postnatal VEGF-induced angiogenesis without affecting developmental blood vessels, effectively delaying cancer growth and suppressing pathological inflammation.

“We believe that the development of drugs that specifically inhibit PTIP-NFAT interaction, as well as epigenomic drugs focused on non-canonical PRC1.3, are expected to lead the way to selective drug discovery that will protect against the vascular diseases found in ageing,” said Dr. Minami.

Source: Kanki et al. (2022). Bivalent-histone-marked immediate-early gene regulation is vital for VEGF-responsive angiogenesis. Cell Reports, 38(6), 110332.

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