Hdac3 regulates lymphovenous and lymphatic valve formation

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...

Celý popis

Uložené v:

Podrobná bibliografia
Vydané v:	The Journal of clinical investigation Ročník 127; číslo 11; s. 4193 - 4206
Hlavní autori:	Janardhan, Harish P., Milstone, Zachary J., Shin, Masahiro, Lawson, Nathan D., Keaney, John F., Trivedi, Chinmay M.
Médium:	Journal Article
Jazyk:	English
Vydavateľské údaje:	United States American Society for Clinical Investigation 01.11.2017
Predmet:	Animals Base Sequence Binding Sites Biomedical research Blood Blood platelets Care and treatment Diagnosis E1A-Associated p300 Protein - metabolism Endothelium Enhancer Elements, Genetic Enzymes Epigenesis, Genetic Epigenetics ETS protein Ets-1 protein GATA2 Transcription Factor - genetics GATA2 Transcription Factor - metabolism Gene expression Gene Expression Regulation, Developmental Genomes Genomics HEK293 Cells Histone acetyltransferase Histone deacetylase Histone Deacetylases - physiology Histones Humans Lethality Leukemia Lymphangiogenesis Lymphatic drainage Lymphatic system Lymphatic System - enzymology Lymphatic Vessels - enzymology Lymphedema Mechanical stimuli Mice, Transgenic Morphogenesis Mutation Rodents Roles Transcription factors
ISSN:	0021-9738, 1558-8238, 1558-8238
On-line prístup:	Získať plný text
Tagy:	Pridať tag Žiadne tagy, Buďte prvý, kto otaguje tento záznam!

Popis
Shrnutí:	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.
Bibliografia:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23
ISSN:	0021-9738 1558-8238 1558-8238
DOI:	10.1172/JCI92852