Functional Analysis Of Mta3/NuRD Complex In Zebrafish Primitive Hematopoiesis

Through vertebrate primitive hematopoiesis, precursor cells give rise to all kinds of primitive blood cells, which provide nutritional factors for embryonic organs and tissues. The whole process of primitive hematopoiesis is under complicated and precise control, and any improper control will cause severe defects of development or malignant diseases. Identification of key regulators in hematopoiesis will help figure out molecular mechanisms underlying each process, build up an entire network, and provide appropriate candidates for clinical treatments. The NuRD deacetylation complex plays important roles in differentiation of erythrocytes and lymphocytes, but its role in primitive hematopoiesis has not been reported before. In this study, using zebrafish as a model system, the potential role of the Mta3/NuRD complex in primitive hematopoiesis has been investigated with a focus on its component Mta3.In our study, it is demonstrated that knockdown of mta3 inhibits the expression of primitive hematopoietic markers gata1 and hbbe3, reduces the number of red blood cells and causes severe defects in primitive hematopoiesis. Overexpression of mta3 mRNA promotes hematopoiesis and rescues blood defects caused by mta3 knockdown. However, down- or up-regulation of mta3 expression has no effect on apoptosis or proliferation of hematopoietic cells. Indeed, mta3 acts upstream of Scl/Lmo2 to specify hematopoietic precursors from hemangioblasts. Treatment with the histone deacetylases inhibitor VPA blocks the promoting effect of mta3 overexpression on primitive hematopoiesis, whereas overexpressions of HDAC1 or MBD3, two other components of NuRD complex, enhances the expression of hematopoietic markers in a way similar to mta3 overexpression. Furthermore, inhibition of histone deacetylase activity by VPA or TSA treatment affects the expression of early hematopoietic master gene scl, which is identical to mta3 knockdown effect. These results suggest that the Mta3/NuRD complex regulates zebrafish primitive hematopoiesis and acts at the top of the regulatory hierarchy of primitive hematopoiesis.In conclusion, this study demonstrates for the first time that, the Mta3/NuRD complex is essential for zebrafish primitive hematopoiesis. The complex regulates the specification of hematopoietic precursors by controlling the initiation of scl expression and acts at the top of the regulatory hierarchy of primitive hematopoiesis. These findings provide new insight into the regulation of vertebrate primitive hematopoiesis, and enrich the regulatory network.