Emberger syndrome (Lymphedema)

Emberger syndrome (Lymphedema) is a lymphatic anomaly, and it is responsible for considerable morbidity, with no current effective treatments. The underlying pathology is often defective lymphatic valve development leading to improper drainage of extravasated protein-rich fluid from the tissues. Recently we revealed how human genetic variants or mutations within evolutionarily conserved non-coding DNA elements alter recruitment of histone deacetylase 3 (Hdac3), thus modifying gene expression to cause lymphedema (The Journal of Clinical Investigation). Our study demonstrates that Hdac3 is essential for lymphatic valve development, thus lymphatic drainage in mice. Hdac3-deficient lymphatic valves exhibit reduced expression of Gata2, which is frequently mutated in patients with Emberger syndrome. In response to extracellular oscillatory shear stress (OSS), Hdac3 functions in a chromatin-dependent, but deacetylase-independent, manner to activate Gata2 expression within lymphatic endothelial cells (LECs), the building blocks of the mammalian lymphatic valves. Mechanistically, the transcription factors Tal1, Gata2, and Ets1/2 physically interacted with and recruited Hdac3 to the evolutionarily conserved (divergence ~350 million years ago) E-box–GATA–ETS composite element of a Gata2 intragenic enhancer in response to OSS. In turn, Hdac3 recruited histone acetyltransferase Ep300 to form an enhanceosome complex that promoted Gata2 expression. Interestingly, mutations within this conserved GATA2 intragenic enhancer reduce GATA2 expression and cause lymphedema (Emberger syndrome) in both humans and mice. These data challenge long-held assumptions that HDACs replace HATs to promote both histone deacetylation and repression of transcription.