Submitted December 24, 2008
Accepted April 22, 2009
Identification of TWSG1 as a second novel erythroid regulator of hepcidin expression in murine and human cells
Toshihiko Tanno, Prashanth Porayette, Orapan Sripichai, Seung-Jae Noh, Colleen Byrnes, Ajoy Bhupatiraju, Y. Terry Lee, Julia B. Goodnough, Omid Harandi, Tomas Ganz, Robert F. Paulson, and Jeffery L. Miller*
Molecular Medicine Branch, NIDDK, NIH, Bethesda, MD, United States
Department of Veterinary and Biomedical Sciences, Center of Molecular Immunology and Infectious Disease, Penn State University, State College, PA, United States
Departments of Medicine and Pathology, University of California, Los Angeles, CA, United States
* Corresponding author; email: jm7f{at}nih.gov.
In thalassemia and other iron loading anemias, ineffective erythropoiesis and erythroid signaling molecules are thought to cause inappropriate suppression of a small peptide produced by hepatocytes named hepcidin. Previously, it was reported that the erythrokine GDF15 is expressed at very high levels in thalassemia and suppresses hepcidin expression. In this study, erythroblast expression of a second molecule named twisted gastrulation (TWSG1) was explored as a potential erythroid regulator of hepcidin. Transcriptome analyses suggest TWSG1 is produced during the earlier stages of erythropoiesis. Hepcidin suppression assays demonstrated inhibition by TWSG1 as measured by quantitative PCR in dosed assays (1-1,000 ng/ml TWSG1). In human cells, TWSG1 suppressed hepcidin indirectly by inhibiting the signaling effects and associated hepcidin upregulation by bone morphogenic proteins 2 and 4 (BMP2 / BMP4). In murine
hepatocytes, hepcidin expression was inhibited by murine Twsg1 in the absence of additional BMP. In vivo studies of Twsg1 expression were performed in healthy and thalassemic mice. Twsg1 expression was significantly increased in the spleen, bone marrow, and liver of the
thalassemic animals. These data demonstrate that twisted gastrulation protein interferes with BMP-mediated hepcidin expression and may act with GDF15 to dysregulate iron homeostasis in thalassemia syndromes.
