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Zbtb14 regulates monocyte and macrophage development through inhibiting pu.1 expression in zebrafish
Yun Deng1,2, Haihong Wang1,2, Xiaohui Liu1,2
1Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Abstract:
Macrophages and their precursor cells, monocytes, are the first line of defense of the body against foreign pathogens and tissue damage. Although the origins of macrophages are diverse, some common transcription factors (such as PU.1) are required to ensure proper development of monocytes/macrophages. Here, we report that the deficiency of zbtb14, a transcription repressor gene belonging to ZBTB family, leads to an aberrant expansion of monocyte/macrophage population in zebrafish. Mechanistically, Zbtb14 functions as a negative regulator of pu.1, and SUMOylation on a conserved lysine is essential for the repression activity of Zbtb14. Moreover, a serine to phenylalanine mutation found in an acute myeloid leukemia (AML) patient could target ZBTB14 protein to autophagic degradation. Hence, ZBTB14 is a newly identified gene implicated in both normal and malignant myelopoiesis.
Insights
Zbtb14 deficiency causes abnormal monocyte/macrophage expansion by regulating PU.1. A mutation linked to acute myeloid leukemia (AML) affects ZBTB14 protein stability, implicating it in myelopoiesis.
Area of Science:
- Immunology and Developmental Biology
- Molecular Genetics and Cancer Research
Background:
- Monocytes and macrophages are crucial immune cells involved in pathogen defense and tissue repair.
- Proper development of monocytes/macrophages relies on specific transcription factors like PU.1.
Purpose of the Study:
- To investigate the role of the transcription repressor gene Zbtb14 in monocyte/macrophage development.
- To elucidate the mechanism by which Zbtb14 regulates myelopoiesis.
- To explore the implications of ZBTB14 in malignant conditions like acute myeloid leukemia (AML).
Main Methods:
- Utilized zebrafish as a model organism to study gene function in vivo.
- Investigated the regulatory relationship between Zbtb14 and PU.1.
- Examined the role of SUMOylation in Zbtb14's transcriptional repression activity.
- Analyzed the impact of an AML-associated mutation on ZBTB14 protein stability and degradation pathways.
Main Results:
- Zebrafish lacking Zbtb14 exhibited an aberrant expansion of the monocyte/macrophage population.
- Zbtb14 acts as a negative regulator of PU.1, a key transcription factor in myelopoiesis.
- SUMOylation of Zbtb14 is essential for its repressive function.
- An AML patient mutation (Serine to Phenylalanine) targets ZBTB14 for autophagic degradation.
Conclusions:
- Zbtb14 is a novel gene that plays a critical role in regulating normal monocyte/macrophage development.
- Dysregulation of Zbtb14, potentially through altered protein stability, is implicated in the pathogenesis of AML.
- ZBTB14 is a newly identified player in both normal and malignant myelopoiesis.
