Wei Xie’s group from School of Life Sciences at Tsinghua University published an article in Molecular cell, reporting the regulation of epigenetic memory and mouse development by a simple isoform switch of TET1 protein.
The research group of Prof. Wei Xie from School of Life Sciences at Tsinghua University published an article in Molecular Cell on December 1st, 2016, entitled “Isoform switch of TET1 regulates DNA demethylation and mouse development”. This work revealed the mechanism how DNA methylation and epigenetic memory between generations are regulated by a simple isoform switch of the methylcytosine oxidase TET1.
DNA methylation is a classic epigenetic modification, which plays crucial roles in regulating transcription, genome stability, development, and genome imprints transmitted through generations. In mammalian genome, DNA methylation is established, maintained and removed through highly regulated pathways. The methylcytosine oxidase TET proteins are involved in the active demethylation process. However, it remains elusive how exactly TET proteins find substrates in the genome for DNA methylcytosine oxidation.
In this paper, by investigating the expression data in different cell types, the researchers found interestingly there are two distinct TET1 isoforms expressed in different developmental stages in mice. The full-length TET1 isoform (TET1e) is restricted to early embryos, embryonic stem cells (mESCs) and primordial germ cells (PGCs). By contrast, a short TET1 isoform (TET1s) is preferentially expressed in somatic cells, which lacks the N-terminus including the CXXC domain, a DNA-binding module. Unexpectedly, TET1s showed a similar binding pattern genomewide to that of TET1e, with preference to CpG islands (CGI) and promoters. Interestingly, further biochemistry assays showed that TET1e has significantly higher global chromatin affinity than that of TET1s. Furthermore, the global chromatin binding, but not targeted binding at CGIs, correlates with TET1-mediated demethylation. Finally, the researchers carefully generated a mouse model with exclusive expression of Tet1s during the whole life cycle. Consequently, they found genomic imprints cannot be properly erased in PGCs of the mutant mice. The removal of imprints in PGCs is necessary to re-establish parent-specific imprints in gametes which will be subsequently transmitted to the next generation. The failure to do so in these mutant mice resulted in developmental defects of their progenies including decreased body weight and partial lethality. In summary, this work showed epigenetic memory between generations is regulated by a simple isoform switch of TET1 in mouse.
The researchers also made another interesting finding in this work. They found DNA demethylation mediated by TET1 occurs well beyond those binding regions of TET1 detected by ChIP-seq. It was believed that this likely reflects the “global binding” of TET1 and the transient interactions between TET1 and its substrates. By contrast, “targeted binding” of TET1 determined by ChIP-seq at promoters is usually related to stable and continual occupancy which plays important roles in transcription regulation. In support of this notion, the N-terminus of TET1 (excluding the CXXC domain) has potent global chromatin affinity, but shows virtually no binding enrichment in ChIP-seq. The C-terminus of TET1 (TET1s) has weak chromatin affinity, but shows clear binding peaks at promoters and CGIs. These data indicate the global binding and targeted binding for a chromatin factor can be separated, and the functional targets for a regulator are not limited to its targeted binding targets determined by ChIP-seq.
Investigator Wei Xie from School of Life Sciences of Tsinghua University is the corresponding author of this paper. Ph.D students Wenhao Zhang and Weikun Xia, both from the CLS program in School of Life Sciences of Tsinghua University, are the co-first authors of this paper. Collaborators include Professors Yong-Hui Jiang’s group at Duke University School of Medicine, Shaorong Gao’s group from School of Life Science and Technology at Tongji University, and Danny Leung group from Division of Life Science at the Hong Kong University of Science and Technology. This project is supported by the funding provided by the National Basic Research Program of China, the National Natural Science Foundation of China, the Tsinghua University Initiative Scientific Research Program, the funding from the THU-PKU Center for Life Sciences and the Youth Thousand Scholar Program of China.
Paper link: http://www.cell.com/molecular-cell/fulltext/S1097-2765(16)30675-X