Human fetal globin gene expression is regulated by LYAR.
Bottom Line: We found that PRMT5 binding on the proximal γ-promoter was LYAR-dependent.We also found that LYAR repressed human fetal globin gene expression in both K562 cells and primary human adult erythroid progenitor cells.Thus, these data indicate that LYAR acts as a novel transcription factor that binds the γ-globin gene, and is essential for silencing the γ-globin gene.
Affiliation: The State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210093, China.Show MeSH
Mentions: In order to examine LYAR protein levels during human erythroid differentiation, we utilized an ex vivo erythroid culture system (20). In this system, purified CD34+ hematopoietic progenitors were first expanded for 6 days followed by differentiation for 12 days in different conditioned media (Figure 5A). As shown in Supplementary Figure S8, this system mimics normal erythroid cell differentiation from undifferentiated blasts at day 0 to orthochromatic normoblasts at day 12 (20,21). By the end of differentiation on day 12, terminal erythroid cells produced great amounts of adult β-globin, low levels of γ-globin and undetectable levels of ϵ-globin (Figure 5B). Of note, γ-globin gene expression was significantly, albeit weakly, induced (Figure 5B). LYAR protein was highly expressed from early (day 3, preproerythroblasts) to mid (day 7, basophilic normoblasts) maturation (Figure 5C). LYAR protein was markedly reduced in more mature (day 9–12) erythroblasts (Figure 5C). The decrease in LYAR protein correlated with the rise of globin mRNA levels during erythroid cell differentiation.
Affiliation: The State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210093, China.