Chromatin occupancy and epigenetic analysis reveal new insights into the function of GATA1 N-terminus in erythropoiesis

Te Ling, Yehudit Birger, Monika J. Stankiewicz, Nissim Ben-Haim, Tomer Kalisky, Avigail Rein, Eitan Kugler, Wei Chen, Chunling Fu, Kevin Zhang, Hiral Patel, Jacek W. Sikora, Young Ah Goo, Neil Kelleher, Lihua Zou, Shai Izraeli and John D. Crispino

Key Points

  • Loss of the N-terminus of GATA1, associated with DBA, alters gene regulation through differential chromatin occupancy and modifications

  • Erythropoiesis in GATA1 mutant embryos can be rescued by haploinsufficiency for GATA2


Mutations in GATA1, which lead to expression of the GATA1s isoform that lacks the GATA1 N-terminus, are seen in patients with Diamond-Blackfan Anemia (DBA). In our efforts to better understand the connection between GATA1s and DBA, we comprehensively studied erythropoiesis in Gata1smice. Defects in yolks sac and fetal liver hematopoiesis included impaired terminal maturation and reduced numbers of erythroid progenitors. RNA-sequencing revealed that both erythroid and megakaryocytic gene expression patterns were altered by the loss of the N-terminus, including aberrant up-regulation of Gata2and Runx1. Dysregulation of global H3K27 methylation was found in the erythroid progenitors upon loss of N-terminus of GATA1. Chromatin binding assays revealed that, despite similar occupancy of GATA1 and GATA1s, there was a striking reduction of H3K27me3 at regulatory elements of the Gata2and Runx1genes. Consistent with the observation that overexpression of GATA2 has been reported to impair erythropoiesis, we found that haploinsufficiency of Gata2rescued the erythroid defects of Gata1sfetuses. Together, our integrated genomic analysis of transcriptomic and epigenetic signatures reveals that, Gata1smice provide novel insights into the role of the N-terminus of GATA1 in transcriptional regulation and red blood cell maturation which may potentially be useful for DBA patients.

  • Submitted April 22, 2019.
  • Revision received August 13, 2019.
  • Accepted August 5, 2019.