Haematologica (Feb 2024)

Enhancement of PRMT6 binding to a novel germline <i>GATA1</i> mutation associated with congenital anemia

  • Yingsi Lu,
  • Qingqing Zhu,
  • Yun Wang,
  • Meiling Luo,
  • Junbin Huang,
  • Qian Liang,
  • Lifen Huang,
  • Jing Ouyang,
  • Chenxin Li,
  • Nannan Tang,
  • Yan Li,
  • Tingting Kang,
  • Yujia Song,
  • Xiaoyu Xu,
  • Liping Ye,
  • Guoxing Zheng,
  • Chun Chen,
  • Chengming Zhu

DOI
https://doi.org/10.3324/haematol.2023.284183
Journal volume & issue
Vol. 999, no. 1

Abstract

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Mutations in the master hematopoietic transcription factor GATA1 are often associated with functional defects in erythropoiesis and megakaryopoiesis. In this study, we identified a novel GATA1 germline mutation (c.1162delGG, p.Leu387Leufs*62) in a patient with congenital anemia and occasional thrombocytopenia. The C-terminal GATA1, a rarely studied mutational region, undergoes frameshifting translation as a consequence of this double-base deletion mutation. To investigate the specific function and pathogenic mechanism of this mutant, in vitro mutant models of stable re-expression cells were generated. The mutation was subsequently validated to cause diminished transcriptional activity of GATA1 and defective differentiation of erythroid and megakaryocytes. Using proximity labeling and mass spectrometry, we identified selective alterations in the proximal protein networks of the mutant, revealing decreased binding to a set of normal GATA1-interaction proteins, including the essential co-factor FOG1. Notably, our findings further demonstrated enhanced recruitment of the protein arginine methyltransferase PRMT6, which mediates histone modification at H3R2me2a and represses transcription activity. We also found an enhanced binding of this mutant GATA1/PRMT6 complex to the transcriptional regulatory elements of GATA1’s target genes. Moreover, treatment of the PRMT6 inhibitor MS023 could partially rescue the inhibited transcriptional and impaired erythroid differentiation caused by the GATA1 mutation. Taken together, our results provide molecular insights into erythropoiesis in which mutation leads to partial loss of GATA1 function and the broader role of PRMT6 and its inhibitor MS023 in congenital anemia, highlighting PRMT6 binding as a negative factor of GATA1 transcriptional activity in aberrant hematopoiesis.