Thyroid hormone regulates hematopoiesis via the TR-KLF9 axis

Area of Science:

• Endocrinology
• Genetics
• Hematology

Background:

• Congenital hypothyroidism (CH) is a common endocrine disorder with unknown mechanisms, often presenting with anemia and immunodeficiency.
• Existing models do not fully recapitulate the complex clinical features of CH, including hematopoietic dysfunction.

Purpose of the Study:

• To develop a severe CH model in Bama miniature pigs that mimics anemia and T lymphopenia.
• To identify the genetic basis of CH and its associated pathologies.
• To elucidate the molecular mechanisms linking CH to hematopoietic dysfunction.

Main Methods:

• Ethylnitrosourea (ENU) mutagenesis was used to create a CH model in Bama miniature pigs.
• Whole-exome sequencing and transcriptome sequencing were employed for genetic and molecular analyses.
• In vivo and in vitro experiments, including zebrafish knockdown studies, were conducted to validate gene function.

Main Results:

• A novel recessive mutation (c.1226A>G) in the dual oxidase 2 (DUOX2) gene was identified as the cause of CH, impairing hydrogen peroxide production and thyroid hormone synthesis.
• Krüppel-like factor 9 (KLF9) was found to be downregulated in the thymus of hypothyroid mutants and directly regulated by thyroid hormone (TH) via the TH receptor (TR).
• KLF9 knockdown in zebrafish embryos disrupted erythroid maturation and T lymphopoiesis, indicating its crucial role in hematopoietic development.

Conclusions:

• The TR-KLF9 axis is identified as a key regulator of hematopoietic development in the context of congenital hypothyroidism.
• The identified DUOX2 mutation and the TR-KLF9 pathway offer insights into the pathogenesis of CH-associated anemia and immunodeficiency.
• This study provides a valuable animal model for investigating CH and suggests potential therapeutic targets for thyroid diseases and related hematopoietic disorders.