RRC ID 61256
著者 Arai D, Hayakawa K, Ohgane J, Hirosawa M, Nakao Y, Tanaka S, Shiota K.
タイトル An epigenetic regulatory element of the Nodal gene in the mouse and human genomes.
ジャーナル Mech Dev
Abstract Nodal signaling plays critical roles during embryonic development. The Nodal gene is not expressed in adult tissues but is frequently activated in cancer cells, contributing to progression toward malignancy. Although several regulatory elements of the Nodal gene have been identified, the epigenetic mechanisms by which Nodal expression is regulated over the long term remain unclear. We found a region exhibiting dynamic changes in DNA methylation at approximately -3.0 kb to -0.4 kb upstream from the transcriptional start site (TSS) that we termed the epigenetic regulatory element (ERE). The ERE was unmethylated in mouse embryonic stem cells (mESCs) but became increasingly methylated in differentiated cells and tissues, concomitant with the downregulation of Nodal mRNA expression. In vitro reporter assays identified an Oct3/4 binding motif within the ERE, indicating that the ERE is responsible for the activation of Nodal in mESCs. Furthermore, the ERE was a target of differentiation-associated Polycomb silencing, and the chromatin condensed when mESCs differentiated to embryoid bodies (EBs). Pharmacological inhibition of PRC2 led to the reactivation of Nodal expression in EBs and mouse embryonic fibroblasts (MEFs). The ERE was also targeted by PRC2 in normal human cells. In NODAL-expressing human cancer cells, accumulation of EZH2 and trimethylation of H3K27 at the ERE were diminished. In conclusion, Nodal is epigenetically controlled through the ERE in the mouse embryo and human cells.
巻・号 136
ページ 143-54
公開日 2015-5-1
DOI 10.1016/j.mod.2014.12.003
PII S0925-4773(14)00089-6
PMID 25528267
MeSH Animals Cell Differentiation / genetics Embryonic Stem Cells / cytology Embryonic Stem Cells / metabolism Epigenesis, Genetic* Genome Genome, Human Humans Mice Nodal Protein / genetics* Nodal Protein / metabolism Octamer Transcription Factor-3 / genetics Octamer Transcription Factor-3 / metabolism Regulatory Sequences, Nucleic Acid / genetics* Signal Transduction / genetics
IF 2.126
リソース情報
ヒト・動物細胞 253G1(HPS0002)