Histone demethylase JMJD3 contributes to epigenetic control of <i>INK4a/ARF</i> by oncogenic RAS

Barradas, Marta; Anderton, Emma; Acosta, Juan Carlos; Li, Si De; Banito, Ana; Rodríguez‐Niedenführ, Marc; Maertens, Goedele N.; Banck, Michaela S.; Zhou, Ming; Walsh, Martin J.; Peters, Gordon; Gil, Jesús

doi:10.1101/gad.511109

Cited by 327 publications

(330 citation statements)

References 35 publications

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“…9c). This was accompanied by increased expression of p16, which has been previously associated with increased epidermal ageing 30 , but not p19 or apoptosis (Supplementary Fig. 13).…”

Section: Loss Of Bmal1 Induces Epidermal Ageingmentioning

confidence: 53%

The circadian molecular clock creates epidermal stem cell heterogeneity

Janich

Pascual

Merlos‐Suárez

et al. 2011

Nature

278

290

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Murine epidermal stem cells undergo alternate cycles of dormancy and activation, fuelling tissue renewal. However, only a subset of stem cells becomes active during each round of morphogenesis, indicating that stem cells coexist in heterogeneous responsive states. Using a circadian-clock reporter-mouse model, here we show that the dormant hair-follicle stem cell niche contains coexisting populations of cells at opposite phases of the clock, which are differentially predisposed to respond to homeostatic cues. The core clock protein Bmal1 modulates the expression of stem cell regulatory genes in an oscillatory manner, to create populations that are either predisposed, or less prone, to activation. Disrupting this clock equilibrium, through deletion of Bmal1 (also known as Arntl) or Per1/2, resulted in a progressive accumulation or depletion of dormant stem cells, respectively. Stem cell arrhythmia also led to premature epidermal ageing, and a reduction in the development of squamous tumours. Our results indicate that the circadian clock fine-tunes the temporal behaviour of epidermal stem cells, and that its perturbation affects homeostasis and the predisposition to tumorigenesis.Epidermal stem cells ensure that skin homeostasis is maintained. Murine epidermal stem cells are located either at the permanent portion of the hair follicle-termed the bulge-and are exclusively responsible for hair cycling [1][2][3][4] ; or at the junction between the epidermis and the hair follicle (isthmus), and feed into the epidermis and sebaceous glands [5][6][7] . In addition, a continuous proliferation of basal interfollicular epidermal cells ensures daily epidermal maintenance 8 .Bulge stem cells undergo bouts of activation followed by periods of dormancy, to establish hair follicle cycling. Robust TGF-b and Bmp signals act as 'activation breaks', rendering bulge cells dormant during the resting phase of the hair cycle (telogen) [9][10][11] . At the onset of the growth phase (anagen), bulge cells respond to Wnt signals by migrating into the lower proliferative hair germ region, where they contribute to follicle growth [12][13][14][15] . Subsequently, at mid-anagen, the bulge undergoes a second round of activation, which replenishes cells lost at the onset of anagen 2,3 . However, the response of bulge stem cells to activating stimuli is a heterogeneous process, as only a subset of them become active during either stage of activation 12,13 . The nature of such niche heterogeneity is currently unknown. Importantly, perturbing the equilibrium between the responsive and non-responsive stem cell states causes tissue malfunction and increases the risk of carcinogenesis [16][17][18][19][20] .Here, we analysed the role of the molecular clock in fine-tuning the function of epidermal stem cells. The mammalian clock machinery anticipates and synchronizes vital functions related to the physiological circadian needs of the organism 21 . The core molecular clock is established by a positive limb, composed of heterodimers of the transcription fa...

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“…9c). This was accompanied by increased expression of p16, which has been previously associated with increased epidermal ageing 30 , but not p19 or apoptosis (Supplementary Fig. 13).…”

Section: Loss Of Bmal1 Induces Epidermal Ageingmentioning

confidence: 53%

The circadian molecular clock creates epidermal stem cell heterogeneity

Janich

Pascual

Merlos‐Suárez

et al. 2011

Nature

278

290

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“…However, we could not detect an activation of p53 or p21 or significant induction of several SASP components. This is reminiscent of the arrest caused by JMJD3 overexpression, which also results in p16 INK4a induction in the absence of activation of p53 (Barradas et al ., 2009). Moreover, it has been described that p16 INK4a induction is sufficient to trigger senescence in the absence of SASP (Coppe et al ., 2011), similar to what we observe upon miR‐9 expression.…”

Section: Discussionmentioning

confidence: 99%

CBX7 and miR‐9 are part of an autoregulatory loop controlling p16^INK^4a

et al. 2015

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SummaryPolycomb repressive complexes (PRC1 and PRC2) are epigenetic regulators that act in coordination to influence multiple cellular processes including pluripotency, differentiation, cancer and senescence. The role of PRCs in senescence can be mostly explained by their ability to repress the INK4/ARF locus. CBX7 is one of five mammalian orthologues of Drosophila Polycomb that forms part of PRC1. Despite the relevance of CBX7 for regulating senescence and pluripotency, we have a limited understanding of how the expression of CBX7 is regulated. Here we report that the miR‐9 family of microRNAs (miRNAS) downregulates the expression of CBX7. In turn, CBX7 represses miR‐9‐1 and miR‐9‐2 as part of a regulatory negative feedback loop. The miR‐9/CBX7 feedback loop is a regulatory module contributing to induction of the cyclin‐dependent kinase inhibitor (CDKI) p16INK 4a during senescence. The ability of the miR‐9 family to regulate senescence could have implications for understanding the role of miR‐9 in cancer and aging.

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“…1A). [14,15]. We generated IMR90 qRT-PCR and immunofluorescence analyses were performed as described previously [36].…”

Section: Resultsmentioning

confidence: 99%

Hypoxic reprograming of H3K27me3 and H3K4me3 at the INK4A locus

et al. 2016

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Activation of Raf reduces the repressive histone mark H3K27me3 at the INK4a locus by inducing the H3K27me3 demethylase JMJD3. During hypoxia, the catalyitc activity of JMJD3 is reduced due to the limited availability of O 2 as a substrate. In our study, we found that hypoxia prevented Raf-induced JMJD3 from demethylating H3K27me3 at the INK4a locus. Nonetheless, hypoxia did not prevent Raf signaling from inducing INK4a mRNA. Interestingly, we found that hypoxia strongly enhanced the active histone mark H3K4me3 at the INK4a locus by inhibiting the H3K4me3 demethylases JARID1A and JARID1B. Therefore, this study demonstrates that the O 2 concentration in the microenvironment differentially affects the repressive methylation on K27 and the activating methylation on K4 at the INK4a locus by inhibiting the H3K27me3 and H3K4me3 demethylases.

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Histone demethylase JMJD3 contributes to epigenetic control of INK4a/ARF by oncogenic RAS

Cited by 327 publications

References 35 publications

The circadian molecular clock creates epidermal stem cell heterogeneity

The circadian molecular clock creates epidermal stem cell heterogeneity

CBX7 and miR‐9 are part of an autoregulatory loop controlling p16^INK^4a

Hypoxic reprograming of H3K27me3 and H3K4me3 at the INK4A locus

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Histone demethylase JMJD3 contributes to epigenetic control of INK4a/ARF by oncogenic RAS

Cited by 327 publications

References 35 publications

The circadian molecular clock creates epidermal stem cell heterogeneity

The circadian molecular clock creates epidermal stem cell heterogeneity

CBX7 and miR‐9 are part of an autoregulatory loop controlling p16INK4a

Hypoxic reprograming of H3K27me3 and H3K4me3 at the INK4A locus

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CBX7 and miR‐9 are part of an autoregulatory loop controlling p16^INK^4a