Open AccessGenetic and epigenetic orchestration of Gfi1aa-Lsd1-cebpα in zebrafish neutrophil development
Author(s) -
Mei Wu,
Yue Xu,
Jing Li,
Jiamei Lian,
Qi Chen,
Ping Meng,
Ting Lü,
Huafeng Xie,
Wenqing Zhang,
Jin Xu,
Yiyue Zhang
Publication year - 2021
Publication title -
development
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.15
H-Index - 36
eISSN - 1477-9129
pISSN - 0950-1991
DOI - 10.1242/dev.199516
Subject(s) - biology , cebpa , zebrafish , granulopoiesis , epigenetics , myelopoiesis , dna methylation , transcription factor , myeloid , genetics , microbiology and biotechnology , phenotype , immunology , cancer research , progenitor cell , gene , stem cell , gene expression
Neutrophils are the most abundant vertebrate leukocytes and they are essential to host defense. Despite extensive investigation, the molecular network controlling neutrophil differentiation remains incompletely understood. GFI1 is associated with several myeloid disorders, but its role and the role of its co-regulators in granulopoiesis and pathogenesis are far from clear. Herein, we demonstrate that zebrafish gfi1aa deficiency induces excessive neutrophil progenitor proliferation, accumulation of immature neutrophils from the embryonic stage, and some phenotypes similar to myelodysplasia syndrome in adulthood. Both genetic and epigenetic analysis demonstrated immature neutrophil accumulation in gfi1aa-deficient mutants to be due to up-regulation of cebpα transcription. Increased transcription was associated with Lsd1 altered H3K4 methylation of cebpα regulatory region. Taken together, results demonstrated Gfi1aa, Lsd1, and cebpα to form a regulatory network that controlled neutrophil development, providing a disease progression traceable model for myelodysplasia syndrome. The use of the model will provide new insights into a molecular understanding of GFI1 related myeloid disorders as well a mean by which to develop targeted therapeutic approaches for treatment.