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Insight into GATA1 transcriptional activity through interrogation of cis elements disrupted in human erythroid disorders

2016; National Academy of Sciences; Volume: 113; Issue: 16 Linguagem: Inglês

10.1073/pnas.1521754113

1091-6490

Aoi Wakabayashi, Jacob C. Ulirsch, Leif S. Ludwig, Claudia Fiorini, Makiko Yasuda, Avik Choudhuri, Patrick McDonel, Leonard I. Zon, Vijay G. Sankaran,

RNA modifications and cancer

Significance Methods for identifying causal variants underlying human diseases have been greatly enhanced by whole-exome sequencing; however, this approach overlooks mutations that occur within noncoding regulatory regions. Moreover, the mechanisms for how such mutations result in disease are poorly understood. In this study, we interrogated binding sites of the blood cell transcription factor GATA1 in regulatory elements that are mutated in cases of human red blood cell disorders by creating small-targeted deletions in model cell lines. These deletions cause a major reduction in target gene expression. We used this initial insight to show that such elements are highly conserved, and that through predictive modeling, we can gain global insight into key determinants of GATA1 transcriptional activity.