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JAK2-mediated Epigenetic Alterations Support the Pluripotency of Mouse ESCs

Review of LIF maintains mouse embryonic stem cells pluripotency by modulating TET1 and JMJD2 activity in a JAK2‐dependent manner from STEM CELLS by Stuart P. Atkinson

Mouse embryonic stem cells (mESCs) represent the in vitro counterparts of the cells of the pre‐implantation epiblast; therefore, understanding how mESCs self-renew and differentiate may aid our understanding of the fate decisions made during early embryonic development. Typical mESC culture conditions include supplementation with leukemia inhibitory factor (LIF), which induces the activation of the signal transducer and activator of transcription 3 (STAT3) transcription factor through the activity of the Janus Kinases (JAKs) [1]. STAT3 then binds to open chromatin regions at regulatory regions associated with core pluripotent genes [2, 3] to induce their expression [4] and support the pluripotent state of mESCs.

In a new STEM CELLS article [5], researchers led by Chang‐Hoon Kim and Sang‐Hun Lee (Hanyang University, Seoul, South Korea) now report that LIF-activated JAK2 interacts with epigenetic enzymes in mESCs to modify DNA methylation and histone patterns to create the open chromatin regions required for pluripotent gene expression. Overall, Wulansari et al. reveal a novel epigenetic regulatory role of JAK2 that supports the maintenance of the pluripotent state of mESCs.

The authors discovered that LIF activation induced the translocation of cytosolic JAK2 into the nucleus of mESCs concomitant with a decrease in DNA methylation, as evidenced by a decrease in 5-methylcytosine levels and an increase in 5-hydroxymethylcytosine levels at the promoters for the Nanog and Oct4 pluripotency-associated genes but not at differentiation-associated genes. The alteration of the chromatin landscape occurred at regions associated with the binding of STAT3, which would thereby support the increased expression of pluripotency-associated genes. The reduction in the levels of repressive histone modifications (trimethylated H3K9 and K27) at similar regions additionally suggested that JAK2 may regulate epigenetic modifiers to allow for LIF-mediated pluripotency. Notably, the pluripotency-inducing effect of LIF disappeared in JAK2-knockout mESCs or following the treatment of wild-type mESCs with a JAK2-specific inhibitor.

Their subsequent analysis established that JAK2 induced passive DNA demethylation in mESCs by promoting the degradation of the DNA methyltransferase proteins and active DNA demethylation by interacting with and activating the Ten-eleven translocation methylcytosine dioxygenase 1 (TET1), which functions in the DNA demethylation pathway, through phosphorylation. JAK2 also directly activated lysine-specific demethylase 4A (KDM4A, also known as JMJD2) via phosphorylation, a trimethylation-specific demethylase.

Overall, these exciting new findings provide evidence for the role of nuclear JAK2 activity as a crucial mediator of LIF‐induced epigenetic modifications that support the pluripotency of mESCs. Can subsequent research confirm a crucial role for JAK2 during development?

For answers to this question and to discover more regarding the mechanism controlling the epigenetic landscape that supports the pluripotent state of mouse embryonic stem cells, stay tuned to the Stem Cells Portal!


References

  1. Onishi K and Zandstra PW, LIF signaling in stem cells and development. Development 2015;142:2230-2236.
  2. Silva J, Barrandon O, Nichols J, et al., Promotion of Reprogramming to Ground State Pluripotency by Signal Inhibition. PLOS Biology 2008;6:e253.
  3. Sim Y-J, Kim M-S, Nayfeh A, et al., 2i Maintains a Naive Ground State in ESCs through Two Distinct Epigenetic Mechanisms. Stem Cell Reports 2017;8:1312-1328.
  4. Fleming JD, Giresi PG, Lindahl-Allen M, et al., STAT3 acts through pre-existing nucleosome-depleted regions bound by FOS during an epigenetic switch linking inflammation to cancer. Epigenetics & Chromatin 2015;8:7.
  5. Wulansari N, Sulistio YA, Darsono WHW, et al., LIF maintains mouse embryonic stem cells pluripotency by modulating TET1 and JMJD2 activity in a JAK2-dependent manner. STEM CELLS 2021;39:750-760.