| RRC ID |
90142
|
| 著者 |
Jiang Y, Ye Y, Zhang X, Yu Y, Huang L, Bao X, Xu X.
|
| タイトル |
Identification and characterization of CHD4-associated eRNA as a novel modulator of fetal hemoglobin levels in β-thalassemia.
|
| ジャーナル |
Biochem Biophys Res Commun
|
| Abstract |
Fetal-to-adult hemoglobin switching is controlled by programmed silencing of γ-globin while the re-activation of fetal hemoglobin (HbF) is an effective strategy for ameliorating the clinical severity of β-thalassemia and sickle cell disease. The identification of enhancer RNAs (eRNAs) related to the fetal (α2γ2) to adult hemoglobin (α2β2) switching remains incomplete. In this study, the transcriptomes of GYPA+ cells from six β-thalassemia patients with extreme HbF levels were sequenced to identify differences in patterns of noncoding RNA expression. It is interesting that an enhancer upstream of CHD4, an HbF-related core subunit of the NuRD complex, was differentially transcribed. We found a significantly positive correlation of eRNA-CHD4 enhancer-gene interaction using the public database of FANTOM5. Specifically, the eRNA-CHD4 expression was found to be significantly higher in both CD34+ HSPCs and HUDEP-2 than those in K562 cells which commonly expressed high level of HbF, suggesting a correlation between eRNA and HbF expression. Furthermore, prediction of transcription binding sites of cis-eQTLs and the CHD4 genomic region revealed a putative interaction site between rs73264846 and ZNF410, a known transcription factor regulating HbF expression. Moreover, in-vitro validation showed that the inhibition of eRNA could reduce the expression of HBG expression in HUDEP-2 cells. Taken together, the findings of this study demonstrate that a distal enhancer contributes to stage-specific silencing of γ-globin genes through direct modulation of CHD4 expression and provide insights into the epigenetic mechanisms of NuRD-mediated hemoglobin switching.
|
| 巻・号 |
701
|
| ページ |
149555
|
| 公開日 |
2024-3-15
|
| DOI |
10.1016/j.bbrc.2024.149555
|
| PII |
S0006-291X(24)00090-1
|
| PMID |
38325179
|
| MeSH |
Adult
Anemia, Sickle Cell* / genetics
Fetal Hemoglobin / genetics
Fetal Hemoglobin / metabolism
Gene Expression Regulation
Humans
Mi-2 Nucleosome Remodeling and Deacetylase Complex / genetics
Mi-2 Nucleosome Remodeling and Deacetylase Complex / metabolism
beta-Thalassemia* / genetics
gamma-Globins / genetics
gamma-Globins / metabolism
|
| リソース情報 |
| ヒト・動物細胞 |
HUDEP-2(RCB4557) |
