ATF7IP/SETDB1-mediated epigenetic programming regulates thymic homing and T lymphopoiesis of hematopoietic progenitors during embryogenesis

T lymphocytes, which are essential for cell-mediated immunity in vertebrates, rely on thymic seeding of lymphoid progenitors for commitment, differentiation and maturation. However, the epigenetic programming of lymphoid-primed progenitor migration and differentiation is incompletely understood. Here, we show that zebrafish embryos lacking the epigenetic modulator Atf7ip or Setdb1 methyltransferase exhibit decreased thymic homing and differentiation of lymphoid progenitor cells. We show that Atf7ip regulates T cell progenitor homing and differentiation via Setdb1-triggered H3K9 trimethylation. Atf7ip interacts with Setdb1 to catalyze H3K9me3 modification of the key immune regulator bach2b to derepress the expression of ccr9a and irf4a, thereby promoting lymphoid progenitor homing and intrathymic differentiation. In the absence of Atf7ip or Setdb1, replenishing irf4a or diminishing bach2b restores the thymic trafficking and differentiation of lymphoid progenitor cells. Notably, depletion of ATF7IP by two complementary cre-recombinase alleles in mice (CAG-CreERT2 and Mx1-iCre) impedes the migration of hematopoietic progenitors to the thymus, resulting in declined T lymphopoiesis. These findings establish the role of ATF7IP/SETDB1-mediated epigenetic programming in governing T lymphoid progenitor trafficking and differentiation, with implications for understanding the pathogenesis of human T lymphoid diseases.