The role of α-ketoglutarate-dependent proteins in pluripotency acquisition and maintenance

Abstract

α-Ketoglutarate is an important metabolic intermediate that acts as a cofactor for several chromatin-modifying enzymes, including histone demethylases and the Tet family of enzymes that are involved in DNA demethylation. In this review, we focus on the function and genomic localization of these α-ketoglutarate-dependent enzymes in the maintenance of pluripotency during cellular reprogramming to induced pluripotent stem cells and in disruption of pluripotency during in vitro differentiation. The enzymatic function of many of these α-ketoglutarate-dependent proteins is required for pluripotency acquisition and maintenance. A better understanding of their specific function will be essential in furthering our knowledge of pluripotency.

Keywords: DNA demethylation; cell differentiation; cell fate; chromatin; epigenetics; histone demethylase; induced pluripotent stem cell (iPS cell) (iPSC); pluripotency; reprogramming; stem cells; α-KG enzymes.

Figure 1.

Pluripotent stem cells can self-renew indefinitely and differentiate into a multitude of cells. Pluripotent cells can be isolated both from the inner cell mass of the blastocyst and the reprogramming of differentiated cells. In the boxes are the α-ketoglutarate–dependent proteins that are known to modulate each process.

Figure 2.

Fe(II) recycling of α-KG–dependent dioxygenases. The catalytic activity of α-KG dioxygenases utilizes oxygen for the decarboxylation of α-KG and oxidation of Fe(II) to Fe(IV), rendering the enzyme inactive. Vitamin C can be used to regenerate iron back to the Fe(II) state, thus restoring catalytic activity.

Figure 3.

A, HIF1 recruits Kdm3a under hypoxic conditions, regulating gene expression by the removal of H3K9me2. B, Kdm2b binds unmethylated CpG islands via a ZF-CXXC domain. Kdm2b is part of the PRC1.1 complex that mediates gene repression through the ubiquitination (Ub) of histone H2A. C, the Kdm4 family of proteins reduce the levels of H3K9me3 at reprogramming-resistant regions, opening the condensed heterochromatin and allowing transcription. D, Kdm5a interacts with the PRC2 complex, removing H3K4me at bivalent genes, leading to gene repression.