O imprinting genômico não permanece estável ao longo do tempo

terça-feira, outubro 04, 2016

Cell Reports

Volume 16, Issue 12, 20 September 2016, Pages 3167–3180

Parent-of-Origin DNA Methylation Dynamics during Mouse Development

Yonatan Stelzer1, Hao Wu1, Yuelin Song1, 2, Chikdu S. Shivalila1, 2, Styliani Markoulaki1, Rudolf Jaenisch1, 2, 3, , 

1 Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA

2 Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA

Received 8 April 2016, Revised 8 August 2016, Accepted 19 August 2016, Available online 20 September 2016 Published: September 20, 2016

Under a Creative Commons license


• In vivo tracing of parent-specific DNA methylation dynamics at single-cell resolution

• Cell-type-specific methylation signatures at the Dlk-Dio3 IG-DMR during development

• Dynamic parent- and cell-type-specific DNA methylation changes in the adult brain


Parent-specific differentially methylated regions (DMRs) are established during gametogenesis and regulate parent-specific expression of imprinted genes. Monoallelic expression of imprinted genes is essential for development, suggesting that imprints are faithfully maintained in embryos and adults. To test this hypothesis, we targeted a reporter for genomic methylation to the imprinted Dlk1-Dio3 intergenic DMR (IG-DMR) to assess the methylation of both parental alleles at single-cell resolution. Biallelic gain or loss of IG-DMR methylation occurred in a small fraction of mouse embryonic stem cells, significantly affecting developmental potency. Mice carrying the reporter in either parental allele showed striking parent-specific changes in IG-DMR methylation, causing substantial and consistent tissue- and cell-type-dependent signatures in embryos and postnatal animals. Furthermore, dynamics in DNA methylation persisted during adult neurogenesis, resulting in inter-individual diversity. This substantial cell-cell DNA methylation heterogeneity implies that dynamic DNA methylation variations in the adult may be of functional importance.