Hdac3 regulates lymphovenous and lymphatic valve formation.

Harish P Janardhan,John F Keaney,Zachary J Milstone,Masahiro Shin,Nathan D Lawson,Chinmay M Trivedi

doi:10.1172/jci92852

Harish P Janardhan, John F Keaney + Show 4 more

Open Access

https://doi.org/10.1172/jci92852

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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.

Highlights

Thin-walled lymphatic capillaries collect interstitial fluid and transport it via collecting lymphatic vessels to the thoracic duct, which in turn drains into the subclavian vein [1]
Our results demonstrate that endothelial inactivation of ubiquitously expressed histone deacetylase 3 (Hdac3), but not Hdac1 or Hdac2, in mice causes embryonic lethality, failure of blood-lymph separation, lymphedema, and defects in both lymphatic and lymphovenous valves
Despite the sequence homology among class I Hdacs, these results suggest a unique function of Hdac3 to mediate bloodlymph separation during development

Summary

Introduction

Thin-walled lymphatic capillaries collect interstitial fluid (lymph) and transport it via collecting lymphatic vessels to the thoracic duct, which in turn drains into the subclavian vein [1]. Oscillatory shear stress (OSS) induces the expression of genes, including GATA2, FOXC2, GJA4, and ITGA9, in LECs that are important for lymphatic valve development [9, 10, 12]. FOXC2, PROX1, GJA4, and ITGA9, is important for blood-lymph separation and the development of lymphovenous and lymphatic valves [9, 10, 13, 14]. Despite this evidence, the mechanisms driving OSS-mediated GATA2 expression during lymphatic valve development remain elusive. Our studies reveal that Hdac3-mediated epigenetic regulation of an OSS-dependent Gata intragenic enhancer orchestrates lymphatic valve development and establishes blood-lymph separation

Results

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