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XB-ART-46264
Dev Dyn. February 1, 2013; 242 (2): 108-21.

Regulation of primitive hematopoiesis by class I histone deacetylases.

Shah RR , Koniski A , Shinde M , Blythe SA , Fass DM , Haggarty SJ , Palis J , Klein PS .


Abstract
Histone deacetylases (HDACs) regulate multiple developmental processes and cellular functions. However, their roles in blood development have not been determined, and in Xenopus laevis a specific function for HDACs has yet to be identified. Here, we employed the class I selective HDAC inhibitor, valproic acid (VPA), to show that HDAC activity is required for primitive hematopoiesis. VPA treatment during gastrulation resulted in a complete absence of red blood cells (RBCs) in Xenopus tadpoles, but did not affect development of other mesodermal tissues, including myeloid and endothelial lineages. These effects of VPA were mimicked by Trichostatin A (TSA), a well-established pan-HDAC inhibitor, but not by valpromide, which is structurally similar to VPA but does not inhibit HDACs. VPA also caused a marked, dose-dependent loss of primitive erythroid progenitors in mouse yolk sac explants at clinically relevant concentrations. In addition, VPA treatment inhibited erythropoietic development downstream of bmp4 and gata1 in Xenopus ectodermal explants. These findings suggest an important role for class I HDACs in primitive hematopoiesis. Our work also demonstrates that specific developmental defects associated with exposure to VPA, a significant teratogen in humans, arise through inhibition of class I HDACs.

PubMed ID: 23184530
PMC ID: PMC3553261
Article link: Dev Dyn.
Grant support: 1R01DA028301 NIDA NIH HHS , 1R01GM076621 NIGMS NIH HHS , 1R01HL110806-01 NHLBI NIH HHS , 1R01HL110806-01 NHLBI NIH HHS , 1R01HL110806-01 NHLBI NIH HHS , 1R01HL110806-01 NHLBI NIH HHS , 1R01HL110806-01 NHLBI NIH HHS , 1R01HL110806-01 NHLBI NIH HHS , P30 CA016520 NCI NIH HHS , P30 CA016520 NCI NIH HHS , P30 CA016520 NCI NIH HHS , P30 CA016520 NCI NIH HHS , P30 CA016520 NCI NIH HHS , P30 CA016520 NCI NIH HHS , R01 DA028301 NIDA NIH HHS , R01 GM076621 NIGMS NIH HHS , R01 HL110806 NHLBI NIH HHS , R01 HL110806 NHLBI NIH HHS , R01 HL110806 NHLBI NIH HHS , R01 HL110806 NHLBI NIH HHS , R01 HL110806 NHLBI NIH HHS , R01 HL110806 NHLBI NIH HHS , R01DK09361 NIDDK NIH HHS , R25 CA101871 NCI NIH HHS , R25 CA101871 NCI NIH HHS , R25 CA101871 NCI NIH HHS , R25 CA101871 NCI NIH HHS , R25 CA101871 NCI NIH HHS , R25 CA101871 NCI NIH HHS , R25 CA101871-07 NCI NIH HHS , R25 CA101871-07 NCI NIH HHS , R25 CA101871-07 NCI NIH HHS , R25 CA101871-07 NCI NIH HHS , R25 CA101871-07 NCI NIH HHS , R25 CA101871-07 NCI NIH HHS

Genes referenced: aplnr bmp4 chrd egr2 gata1 hdac3 hoxb9 lhx1 mpo myod1 ncam1 nkx2-5 nog odc1 otx2 post ptpn11 rax runx1 snai2 t tal1 tbx20 ventx2.2
Antibodies referenced:
Morpholinos referenced:
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