GATA binding protein 2 mediated ankyrin repeat domain containing 26 high expression in myeloid-derived cell lines

BACKGROUND

Thrombocytopenia 2, an autosomal dominant inherited disease characterized by moderate thrombocytopenia, predisposition to myeloid malignancies and normal platelet size and function, can be caused by 5’-untranslated region (UTR) point mutations in ankyrin repeat domain containing 26 (ANKRD26). Runt related transcription factor 1 (RUNX1) and friend leukemia integration 1 (FLI1) have been identified as negative regulators of ANKRD26. However, the positive regulators of ANKRD26 are still unknown.

AIM

To prove the positive regulatory effect of GATA binding protein 2 (GATA2) on ANKRD26 transcription.

METHODS

Human induced pluripotent stem cells derived from bone marrow (hiPSC-BM) and urothelium (hiPSC-U) were used to examine the ANKRD26 expression pattern in the early stage of differentiation. Then, transcriptome sequencing of these iPSCs and three public transcription factor (TF) databases (Cistrome DB, animal TFDB and ENCODE) were used to identify potential TF candidates for ANKRD26. Furthermore, overexpression and dual-luciferase reporter experiments were used to verify the regulatory effect of the candidate TFs on ANKRD26. Moreover, using the GENT2 platform, we analyzed the relationship between ANKRD26 expression and overall survival in cancer patients.

RESULTS

In hiPSC-BMs and hiPSC-Us, we found that the transcription levels of ANKRD26 varied in the absence of RUNX1 and FLI1. We sequenced hiPSC-BM and hiPSC-U and identified 68 candidate TFs for ANKRD26. Together with three public TF databases, we found that GATA2 was the only candidate gene that could positively regulate ANKRD26. Using dual-luciferase reporter experiments, we showed that GATA2 directly binds to the 5’-UTR of ANKRD26 and promotes its transcription. There are two identified binding sites of GATA2 that are located 2 kb upstream of the TSS of ANKRD26. In addition, we discovered that high ANKRD26 expression is always related to a more favorable prognosis in breast and lung cancer patients.

CONCLUSION

We first discovered that the transcription factor GATA2 plays a positive role in ANKRD26 transcription and identified its precise binding sites at the promoter region, and we revealed the importance of ANKRD26 in many tissue-derived cancers.

Key Words: Ankyrin repeat domain containing 26, GATA binding protein 2, Thrombocytopenia 2, Transcriptional regulation, Myeloid-derived cell lines

Core Tip: The 5’-untranslated region mutation of ankyrin repeat domain containing 26 (ANKRD26) plays an important role in the pathology of thrombocytopenia 2 (THC2). Considering the predisposition of THC2 patients to myeloid malignancies, further revealing the molecular mechanism of ANKRD26 transcription is warranted. Although Runt related transcription factor 1 and friend leukemia integration 1 have been shown to negatively regulate ANKRD26 expression, no known positive regulators have been reported. Here, we first revealed that GATA binding protein 2 mediates high ANKRD26 expression by binding to its promoter region. We discovered that high ANKRD26 expression was always associated with favorable overall survival. Our study provides insights into the regulatory network of ANKRD26 and the pathological process of THC2.

• Citation: Jiang YZ, Hu LY, Chen MS, Wang XJ, Tan CN, Xue PP, Yu T, He XY, Xiang LX, Xiao YN, Li XL, Ran Q, Li ZJ, Chen L. GATA binding protein 2 mediated ankyrin repeat domain containing 26 high expression in myeloid-derived cell lines. World J Stem Cells 2024; 16(5): 538-550
• URL: https://www.wjgnet.com/1948-0210/full/v16/i5/538.htm
• DOI: https://dx.doi.org/10.4252/wjsc.v16.i5.538