Hdac3 regulates lymphovenous and lymphatic valve formation

Abstract

Lymphedema, the most common lymphatic anomaly, involves defective lymphatic valve development; yet the epigenetic modifiers underlying lymphatic valve morphogenesis remain elusive. Here, we showed that during mouse development, the histone-modifying enzyme histone deacetylase 3 (Hdac3) regulates the formation of both lymphovenous valves, which maintain the separation of the blood and lymphatic vascular systems, and the lymphatic valves. Endothelium-specific ablation of Hdac3 in mice led to blood-filled lymphatic vessels, edema, defective lymphovenous valve morphogenesis, improper lymphatic drainage, defective lymphatic valve maturation, and complete lethality. Hdac3-deficient lymphovenous valves and lymphatic vessels exhibited reduced expression of the transcription factor Gata2 and its target genes. In response to oscillatory shear stress, the transcription factors Tal1, Gata2, and Ets1/2 physically interacted with and recruited Hdac3 to the evolutionarily conserved E-box–GATA–ETS composite element of a Gata2 intragenic enhancer. In turn, Hdac3 recruited histone acetyltransferase Ep300 to form an enhanceosome complex that promoted Gata2 expression. Together, these results identify Hdac3 as a key epigenetic modifier that maintains blood-lymph separation and integrates both extrinsic forces and intrinsic cues to regulate lymphatic valve development.

Piezo1 incorporates mechanical force signals into the genetic program that governs lymphatic valve development and maintenance

“…Fluid flow is known to play a key role in vascular development and morphogenesis (5). In particular, OSS has been reported to upregulate the lymphatic valve-associated genes, such as FOXC2, GATA2, CX37, LAMA5, and ITGA9, and to induce cellular morphology change (15)(16)(17)(18)(19)(20)(21)(22). We thus investigated how the mechanosensor Piezo1 affects the mechanotransduction process by performing in vitro loss-of-function studies.…”

“…Because of malformations or injuries, diseased lymphatic valves often lead to severe lymphatic pathologies. Recent studies demonstrated that fluid flow-derived physical signal significantly controls lymphatic valve development through mechanotransduction pathways and identified key molecular players essential for the pathways (15)(16)(17)(18)(19)(20)(21)(22). In this study, we defined the crucial role of the cell stretch sensor Piezo1 in incorporating the flow-mediated physical signal into the genetic program controlling lymphatic valve development.…”

“…Previous studies have dissected mechanotransduction pathways that control different aspects of vascular pathophysiology (9)(10)(11)(12)(13)(14). In particular, recent work has elegantly identified and characterized important molecular constituents in lymphatic valve formation (15)(16)(17)(18)(19)(20)(21)(22). Notably, these molecular players, intricately controlled by fluid flow-generated oscillating shear stress (OSS), cooperatively orchestrate the genetic and epigenetic programs responsible for the development, function, and maintenance of lymphatic valves.…”

Epigenetic priming by Dot1l in lymphatic endothelial progenitors ensures normal lymphatic development and function

“…FAO enhancement is mediated by Prox1-targeted Cpt1a expression and leads to the production of mitochondrial acetyl-CoA, which can function as a cofactor of p300mediated histone acetylation. Loss of function of mouse Hdac3 reduced lymphatic valve formation and blood-lymphatic mixing, with aberrant gene transcription 29 . Therefore, our data and others suggest that transcriptional control by epigenetic mechanisms is essential for lymph vessel formation and function.…”

“…Another chromatin remodeler, chromodomain helicase DNAbinding protein 4 (Chd4), is essential for LEC integrity by regulating urokinase plasminogen activator receptor (uPAR) expression 27 . In addition, histone deacetylase 3 (Hdac3) function is required for lymphatic valve formation by regulating Gata2 expression in response to shear stress 29 . Recently, histone acetyltransferase p300 was shown to promote LEC specification through the activation of lymphatic genes that are critical to the process of blood EC (BEC)-to-LEC differentiation 30 .…”