Transient ectopic expression of the histone demethylase JMJD3 accelerates the differentiation of human pluripotent stem cells

Abstract

Harnessing epigenetic regulation is crucial for the efficient and proper differentiation of pluripotent stem cells (PSCs) into desired cell types. Histone H3 lysine 27 trimethylation (H3K27me3) functions as a barrier against cell differentiation through the suppression of developmental gene expression in PSCs. Here, we have generated human PSC (hPSC) lines in which genome-wide reduction of H3K27me3 can be induced by ectopic expression of the catalytic domain of the histone demethylase JMJD3 (called JMJD3c). We found that transient, forced demethylation of H3K27me3 alone triggers the upregulation of mesoendodermal genes, even when the culture conditions for the hPSCs are not changed. Furthermore, transient and forced expression of JMJD3c followed by the forced expression of lineage-defining transcription factors enabled the hPSCs to activate tissue-specific genes directly. We have also shown that the introduction of JMJD3c facilitates the differentiation of hPSCs into functional hepatic cells and skeletal muscle cells. These results suggest the utility of the direct manipulation of epigenomes for generating desired cell types from hPSCs for cell transplantation therapy and platforms for drug screenings.

Dynamics of chromatin marks and the role of JMJD3 during pancreatic endocrine cell fate commitment

“…Jmjd3 regulates the transition from Ngn3-low to Only two histone demethylases, JMJD3 and UTX, have been proved to be responsible for the removal of H3K27me3 mark (Agger et al, 2007;Lan et al, 2007). Studies have indicated that JMJD3 regulates promoter-specific H3K27me3 levels in human ES cells (Akiyama et al, 2016). Hence, we examined whether the precocious loss of Jmjd3 expression would affect cell fate commitment from Ngn3-low to Ngn3-high.…”

The histone demethylase Jmjd3 regulates zebrafish myeloid development by promoting spi1 expression

“…Previous studies and our research showed that Jmjd3 is required for the activation of mammalian developmental programs through a demethylation-activity-dependent mechanism [22, 27–29]. Interestingly, other groups have demonstrated that Jmjd3 also functions independently of its enzymatic activity [66, 67].…”

“…Jumonji domain-containing protein D3 (Jmjd3, also named Kdm6b) is a member of the H3K27me3/2-specific demethylase family that promotes gene transcription by acting as a rival of the Polycomb repressive complex 2 (PRC2) [22, 23]. Studies using embryonic stem cells suggest that Jmjd3 is required for the development of all three germ layers [24–26], Jmjd3 accelerates the specification of pluripotent cells by removing H3K27me3 barriers [27]. It has also been shown that Jmjd3 function is necessary for the differentiation and proliferation of cells in different tissues, such as neurons, epidermal cells, cardiac cells, M2 macrophages and T cells [23, 25, 28–30].…”

Temporal scaling in developmental gene networks by epigenetic timing control

“…Our gene network modeling leads us to propose that epigenetic-modifying factors act as master controllers of developmental speed and organism size ( Figure 6D-E networks Lee et al, 2006) ; consequently, the developmental schedules set by these networks could then be uniformly scaled by simply varying the activity of a single chromatin regulator acting globally on all network nodes. Consistent with this idea, disruptions in polycomb complex activity have been shown to accelerate differentiation across multiple cell lineages in different contexts (Akiyama et al, 2016;Endoh et al, 2017;Ezhkova et al, 2009;Fujimura et al, 2018;Jacobsen et al, 2017;Zhang et al, 2015) . In particular, deletion of the PRC2 methyltransferase Ezh2 accelerates the temporal schedule for cerebral corticogenesis, leading to reduced cortical tissue size while preserving the temporal order of neuronal subtype differentiation (Pereira et al, 2010) .…”