Unknown

Dataset Information

0

HIF-1 directly induces TET3 expression to enhance 5-hmC density and induce erythroid gene expression in hypoxia.


ABSTRACT: In mammalian cells, cytosines found within cytosine guanine dinucleotides can be methylated to 5-methylcytosine (5-mC) by DNA methyltransferases and further oxidized by the Ten-eleven translocation dioxygenase (TET) enzymes to 5-hydroxymethylcytosine (5-hmC). We have previously shown that hematopoietic stem and progenitor cells (HSPCs) with TET2 mutations have aberrant 5-hmC distribution and less erythroid differentiation potential. However, these experiments were performed under standard tissue culture conditions with 21% oxygen (O2), whereas HSPCs in human bone marrow reside in ∼1% O2. Therefore, to model human erythropoiesis more accurately, we compared 5-hmC distribution and gene expression in hypoxic vs normoxic conditions. Despite TET enzymes having limited O2 as a substrate in hypoxia, 5-hmC peaks were more numerous and pronounced than in normoxia. Among the TET genes, TET3 was upregulated specifically in hypoxia. We identified 2 HIF-1 binding sites in TET3 by chromatin immunoprecipitation of HIF-1α followed by sequencing, and TET3 upregulation was abrogated with deletion of both sites, indicating that TET3 is a direct HIF-1 target. Finally, we showed that loss of one or both of these HIF-1 binding sites in K562 cells disrupted erythroid differentiation in hypoxia and lowered cell viability. This work provides a molecular link between O2 availability, epigenetic modification of chromatin, and erythroid differentiation.

SUBMITTER: Cao JZ 

PROVIDER: S-EPMC7362358 | biostudies-literature |

REPOSITORIES: biostudies-literature

Similar Datasets

2020-02-01 | GSE142869 | GEO
2020-02-01 | GSE142870 | GEO
2020-02-01 | GSE142867 | GEO
2020-02-01 | GSE142865 | GEO
| S-EPMC9665154 | biostudies-literature
| PRJNA598718 | ENA
| PRJNA598714 | ENA
| PRJNA598712 | ENA
| PRJNA598710 | ENA
2022-08-10 | GSE167478 | GEO