| First Author | Zhang Y | Year | 2017 |
| Journal | Nucleic Acids Res | Volume | 45 |
| Issue | 2 | Pages | 657-671 |
| PubMed ID | 28123038 | Mgi Jnum | J:249615 |
| Mgi Id | MGI:5922703 | Doi | 10.1093/nar/gkw901 |
| Citation | Zhang Y, et al. (2017) Intron 1 GATA site enhances ALAS2 expression indispensably during erythroid differentiation. Nucleic Acids Res 45(2):657-671 |
| abstractText | The first intronic mutations in the intron 1 GATA site (int-1-GATA) of 5-aminolevulinate synthase 2 (ALAS2) have been identified in X-linked sideroblastic anemia (XLSA) pedigrees, strongly suggesting it could be causal mutations of XLSA. However, the function of this int-1-GATA site during in vivo development remains largely unknown. Here, we generated mice lacking a 13 bp fragment, including this int-1-GATA site (T AGATAA: AGCCCC) and found that hemizygous deletion led to an embryonic lethal phenotype due to severe anemia resulting from a lack of ALAS2 expression, indicating that this non-coding sequence is indispensable for ALAS2 expression in vivo Further analyses revealed that this int-1-GATA site anchored the GATA site in intron 8 (int-8-GATA) and the proximal promoter, forming a long-range loop to enhance ALAS2 expression by an enhancer complex including GATA1, TAL1, LMO2, LDB1 and Pol II at least, in erythroid cells. However, compared with the int-8-GATA site, the int-1-GATA site is more essential for regulating ALAS2 expression through CRISPR/Cas9-mediated site-specific deletion. Therefore, the int-1-GATA site could serve as a valuable site for diagnosing XLSA in cases with unknown mutations. |
