Thyroid hormone regulates hematopoiesis via the TR-KLF9 axis

Ying Zhang, Yuanyuan Xue, Chunwei Cao, Jiaojiao Huang, Qianlong Hong, Tang Hai, Qitao Jia, Xianlong Wang, Guosong Qin, Jing Yao, Xiao Wang, Qiantao Zheng, Rui Zhang, Yongshun Li, Ailing Luo, Nan Zhang, Guizhi Shi, Yanfang Wang, Hao Ying, Zhonghua Liu, Hongmei Wang, Anming Meng, Qi Zhou, Hong Wei, Feng Liu and Jianguo Zhao

Key Points

  • A severe hypothyroid pig model created by ENU mutagenesis manifests the clinical features of human patients.

  • KLF9 acts as a critical mediator between the thyroid axis and hematopoiesis.

Publisher's Note: There is an Inside Blood Commentary on this article in this issue.


Congenital hypothyroidism (CH) is one of the most prevalent endocrine diseases, for which the underlying mechanisms remain unknown; it is often accompanied by anemia and immunodeficiency in patients. Here, we created a severe CH model together with anemia and T lymphopenia to mimic the clinical features of hypothyroid patients by ethylnitrosourea (ENU) mutagenesis in Bama miniature pigs. A novel recessive c.1226A>G transition of the dual oxidase 2 (DUOX2) gene was identified as the causative mutation. This mutation hindered the production of hydrogen peroxide (H2O2) and thus contributed to thyroid hormone (TH) synthesis failure. Transcriptome sequencing analysis of the thymuses showed that Krüppel-like factor 9 (KLF9) was predominantly downregulated in hypothyroid mutants. KLF9 was verified to be directly regulated by TH in a TH receptor (TR)-dependent manner both in vivo and in vitro. Furthermore, knockdown of klf9 in zebrafish embryos impaired hematopoietic development including erythroid maturation and T lymphopoiesis. Our findings suggest that the TR-KLF9 axis is responsible for the hematopoietic dysfunction and might be exploited for the development of novel therapeutic interventions for thyroid diseases.

  • Submitted May 4, 2017.
  • Accepted September 6, 2017.
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