Functional Analysis Of Arid2 In Hematopoiesis

Hematopoiesis is the process that all mature blood cells are generated by the Hematopoietic stem and progenitor cells(HSPCs)expansion and differentiation.Hematopoietic stem cells(HSCs)possess two fundamental characteristics,the capacity for self-renewal and the sustained production of all blood cell lineages.These two opposing characteristics are finely orchestrated by epigenetic regulators and cell specific transcriptional factors such as SCL/tal,Runxl,Lmo2,Bmil,Gfil,and GATA2.Epigenetics is the study of heritable changes in gene activity that are not attributable to alterations in genomic sequence including chromatin remodeling,DNA methylation,histone modification,X chromosome inactivation,and non-coding RNA regulation.SWI/SNF complexes have been divided into two main types,depending on their subunits composition:BAF complex contains either BAF250a(encoded by the ARID 1A gene)or BAF250b(encoded by the ARID 1B gene)subunits;PBAF complex contains BAF 180(encoded by the PBRM1 gene)and BAF200(encoded by the ARID2 gene,known as Arid2 in mice)subunits.Several studies have revealed that some subunits of SWI/SNF complexes including BRG1,BAF53a,BAF45a,BAF 180,and BAF250a play pivotal roles in hematopoiesis,but their phenotypes are different,so it is still unclear about the specific role of SWI/SNF complexes in hematopoiesis.Arid2 subunit is restricted to PBAF complex.In mouse model,Arid2 is essential for heart morphogenesis and coronary artery development,but its function in hematopoiesis is still unknown.To further clarify the function of SWI/SNF complexes in hematopoiesis,we generated mouse models with conditional Arid2 gene deletion in the hematopoietic system using Tie2-cre and Vav-icre transgenic mice.TIe2-cre+,Arid2f/f mice displayed embryonic lethality with anemia due to defects in definitive erythropoiesis of the fetal liver.Tie2-crer,Aridf/f mice also showed decreased fetal liver LT-HSCs number.In competitive transplantation assay,fetal liver HSCs from Tie2-cre+,Arid2f/f embryos showed impaired long term reconstitution potential.However,the Vav-icre+,Arid2f/f mice were born alive at nearly expected Mendelian frequencies with an appearance indistinguishable from their wild-type controls.Vav-icre+,Arid2f/f adult mice showed decreased hematopoietic stem and progenitor cells(HSPCs)in bone marrow but increased HSPCs in spleen.Fetal liver cells and bone marrow cells from Vav-icre+,Arid2f/f mice also showed impaired long term reconstitution potential.Then the RNA-seq assays were performed,we found that Arid2 could regulate the expression of some hematopoiesis associated genes.Together,we demonstrate that Arid2 is required for the fetal and adult hematopoiesis.