Table 2.
Non-histone substrates of LSD1. Name of the substrate, the effect of Lys demethylation and the role (if any) in ESCs are depicted.
| Substrate | K Position | Effect | Role in ESCs | References |
|---|---|---|---|---|
| E2F1 | 185 | Stabilization of E2F1 and activation of proapoptotic genes. | N/A | [64,65] |
| DNMT1 | 1096 and 142 | Removal of the methyl group from K1096 (mouse), K1094 (human), and K142 of DNMT1 increases stability. K142 demethylation in the S-phase promotes stability by restricting L3MBTL3-CRL4DCAF5-mediated proteolysis. | DNMT1 is essential for ESCs cell viability and surveillance by controlling DNA methylation. | [10,66] |
| p53 | 370 | Inhibition of the transcriptional activity of p53. | Upon DNA damage, activated p53 represses the core ESC transcriptome and induces the expression of lineage-specific markers. p53 is a transcriptional regulator which suppresses Nanog expression during ESCs differentiation. | [9,67] |
| MEF2D | 267 | Enhances its transcriptional activity. | Promotes myogenic differentiation. | [68] |
| ERa | 266 | Demethylation of K266 allows subsequent acetylation leading to activating of ERα target genes. | N/A | [69] |
| HSP90 | 615 | It promotes HSP90 degradation. | It regulates pluripotency by: (i) regulating OCT4, NANOG and pSTAT3 expression and prevention of proteasomal-mediated degradation of OCT4 and NANOG; (ii) modulating Oct4 mRNA, particularly restraining ESC from mesoderm differentiation. | [70,71] |
| AGO2 | 726 | Stabilization | Its expression promotes an accelerated differentiation by increasing let-7 microRNAs which inhibits Trim71 translation. | [72,73] |
| HIF-1a | 391 | Demethylation of HIF1α at K391 prevents proteasomal-mediated degradation and PHD2-induced hydroxylation, thereby enhancing transcriptional activity of HIF1α to facilitate VEGF expression. | Activated HIF1α enhances the glycolytic program leading to efficient reprogramming. It also sustains self-renewal of iPSCs through regulating Actl6a and acetylation. Inhibition of HIF1α promotes endoderm and mesoderm differentiation. | [74,75] |
| MTA1 | 532 | K532 demethylation disorganizes the formation of the NuRD repressor complex. Unmethylated MTA1 promotes acetylation of demethylated histone H3K9 shifting gene repression to activation. | MTA1 forms a complex with NANOG and POU5F1 known as a NODE. MTA1 deficiency upregulates the expression of endoderm-associated markers. | [76,77] |
| STAT3 | 140 | K140 demethylation enhances transcriptional activity in response to IL-6. | STAT 3 controls Myc expression, promoting self-renewal and pluripotency in ESCs. Its activation is essential for the reprogramming of terminally differentiated cells. | [78,79,80] |
| MYPT1 | 442 | K442 demethylation destabilizes MYPT1 and increases RB1 phosphorylation leading to cell cycle progression. | N/A | [81] |
| OCT4 | 222 | Prevents proteasome independent degradation and refrains the ‘locked-in’ mode binding of OCT4 homodimers which enhances the expression of target genes. | OCT4 is a core pluripotency factor. | [82,83,84,85] |
| UHRF1 | 385 | K385 demethylation stabilizes UHRF1. | It associates with Setd1a/COMPASS complex to maintain mesoderm and neuroectoderm histone marks, ensuring a proper differentiation in stem cells. In association with the Setd1a/COMPASS complex, UHRF1 aids in the regulation of H3K4me3 and H3K27me3 methylation. The maintenance of bivalent histone marks ensures efficient mesoderm and ectoderm differentiation. |
[86,87,88] |