Activation of Neuronal Gene Expression by the JMJD3 Demethylase Is Required for Postnatal and Adult Brain Neurogenesis

Park, Dae Hwi; Hong, Sung Jun; Salinas, Ryan; Liu, Siyuan John; Sun, Shawn W.; Sgualdino, Jacopo; Testa, Giuseppe; Matzuk, Martin M.; Iwamori, Naoki; Lim, Daniel A.

doi:10.1016/j.celrep.2014.07.060

Cited by 122 publications

(105 citation statements)

References 38 publications

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“…The putative role of JMJD3 as an oncogene in cancer development is confirmed by the high expression of JMJD3 in prostate, renal cell and breast carcinomas, and other tumors relative to normal tissues (7,(17)(18)(19). Our study describes a novel function of JMJD3 in hepatocellular carcinoma metastasis by promoting two essential characteristics of metastatic disease in hepatocellular carcinomas, namely, EMT and stemness.…”

Section: Discussionmentioning

confidence: 66%

Aberrant JMJD3 Expression Upregulates Slug to Promote Migration, Invasion, and Stem Cell–Like Behaviors in Hepatocellular Carcinoma

Tang

et al. 2016

Cancer Research

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The Jumonji domain-containing chromatin remodeling factor JMJD3 has important roles in development and cancer. Here, we report a pivotal role for JMJD3 in sustaining the phenotype of aggressive hepatocellular carcinomas. Expression levels of JMJD3 in clinical specimens of hepatocellular carcinoma correlated inversely with patient survival. In hepatocellular carcinoma cells, we found that enforcing its overexpression induced epithelial-mesenchymal transition (EMT), invasive migration, stem cell-like traits, and metastatic properties. Conversely, silencing JMJD3 in hepatocellular carcinoma cells overexpressing it inhibited these aggressive phenotypes. Mechanistically, JMJD3 modulated H3K27me3 in the SLUG gene promoter, a histone mark associated with active SLUG transcription. SLUG silencing blocked JMJD3-induced EMT, stemness, and metastasis. Furthermore, SLUG expression in hepatocellular carcinoma clinical specimens correlated positively with JMJD3 expression. Our results establish JMJD3 as a critical driver of hepatocellular carcinoma stem cell-like and metastatic behaviors, with implications for prognosis and treatment. Cancer Res; 76(22); 6520-32. Ó2016 AACR.

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Section: Discussionmentioning

confidence: 66%

Aberrant JMJD3 Expression Upregulates Slug to Promote Migration, Invasion, and Stem Cell–Like Behaviors in Hepatocellular Carcinoma

Tang

et al. 2016

Cancer Research

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“…Transcriptional enhancers can exist in a "poised" state, having enrichment of H3K27me3 (Rada-Iglesias et al 2011), and in V-SVZ NSCs, the I12b enhancer of Dlx2 exhibits a poised chromatin signature (Park et al 2014). With conditional deletion of Jmjd3, I12b remains enriched with H3K27me3 in V-SVZ NSCs, and Dlx2-dependent neurogenesis fails.…”

Section: Polycomb Group and Trithorax Group Chromatin-modifying Factomentioning

confidence: 99%

The Adult Ventricular–Subventricular Zone (V-SVZ) and Olfactory Bulb (OB) Neurogenesis

Lim

Alvarez-Buylla

2016

Cold Spring Harb Perspect Biol

491

428

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A large population of neural stem/precursor cells (NSCs) persists in the ventricular-subventricular zone (V-SVZ) located in the walls of the lateral brain ventricles. V-SVZ NSCs produce large numbers of neuroblasts that migrate a long distance into the olfactory bulb (OB) where they differentiate into local circuit interneurons. Here, we review a broad range of discoveries that have emerged from studies of postnatal V-SVZ neurogenesis: the identification of NSCs as a subpopulation of astroglial cells, the neurogenic lineage, new mechanisms of neuronal migration, and molecular regulators of precursor cell proliferation and migration. It has also become evident that V-SVZ NSCs are regionally heterogeneous, with NSCs located in different regions of the ventricle wall generating distinct OB interneuron subtypes. Insights into the developmental origins and molecular mechanisms that underlie the regional specification of V-SVZ NSCs have also begun to emerge. Other recent studies have revealed new cellintrinsic molecular mechanisms that enable lifelong neurogenesis in the V-SVZ. Finally, we discuss intriguing differences between the rodent V-SVZ and the corresponding human brain region. The rapidly expanding cellular and molecular knowledge of V-SVZ NSC biology provides key insights into postnatal neural development, the origin of brain tumors, and may inform the development regenerative therapies from cultured and endogenous human neural precursors. N ew neurons continue to be added throughout life to the olfactory bulb (OB) in the brain of many mammals. In rodents, the adult germinal region for OB neurogenesis is located along the walls of the brain lateral ventricles. Recent results regarding the spatial arrangement and cellular morphology of the primary neural precursors-or, neural stem cells (NSCs)-indicate that this region has characteristics similar to both the embryonic ventricular zone (VZ) and subventricular zone (SVZ). Given this new understanding, we now refer to this region as the ventricular-subventricular zone (V-SVZ).Neuroblasts born from NSCs in the mouse V-SVZ migrate rostrally into the OB where they then disperse radially and differentiate into functional interneurons (Fig. 1). Several distinct interneuron subtypes are generated by the V-SVZ, and estimates indicate that thousands of new OB neurons are generated every day in the young adult rodent brain.

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“…All DNA constructs used in this study have been described previously (27,28,54,55). Jetprime transfection reagent has been shown previously to mediate efficient transfection of murine neuronal stem cells (53). Briefly, pCMV10-Myc RIT1Q79L or empty pCMV10 (1 g) vector was mixed with 2 l/g Jetprime reagent according to the protocol of the manufacturer.…”

Section: Methodsmentioning

confidence: 99%

“…Cell Transfections and Treatments-For HNPC transfections, fresh neurospheres were passaged, and ϳ10 5 cells were plated on poly-D-lysine-coated 12/18-mm coverglasses after appropriate sterilization using nitric acid and repeated autoclaving (53). Cells were transfected 72 h using Jetprime transfection reagent after the initial plating, which is necessary for HNPCs to regain contact.…”

Section: Methodsmentioning

confidence: 99%

RIT1 GTPase Regulates Sox2 Transcriptional Activity and Hippocampal Neurogenesis

Mir

Cai

Andres

2017

Journal of Biological Chemistry

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Edited by Paul E. FraserAdult neurogenesis, the process of generating mature neurons from neuronal progenitor cells, makes critical contributions to neural circuitry and brain function in both healthy and disease states. Neurogenesis is a highly regulated process in which diverse environmental and physiological stimuli are relayed to resident neural stem cell populations to control the transcription of genes involved in self-renewal and differentiation. Understanding the molecular mechanisms governing neurogenesis is necessary for the development of translational strategies to harness this process for neuronal repair. Here we report that the Ras-related GTPase RIT1 serves to control the sequential proliferation and differentiation of adult hippocampal neural progenitor cells, with in vivo expression of active RIT1 driving robust adult neurogenesis. Gene expression profiling analysis demonstrates increased expression of a specific set of transcription factors known to govern adult neurogenesis in response to active RIT1 expression in the hippocampus, including sex-determining region Y-related HMG box 2 (Sox2), a well established regulator of stem cell self-renewal and neurogenesis. In adult hippocampal neuronal precursor cells, RIT1 controls an Akt-dependent signaling cascade, resulting in the stabilization and transcriptional activation of phosphorylated Sox2. This study supports a role for RIT1 in relaying niche-derived signals to neural/stem progenitor cells to control transcription of genes involved in self-renewal and differentiation.

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Activation of Neuronal Gene Expression by the JMJD3 Demethylase Is Required for Postnatal and Adult Brain Neurogenesis

Cited by 122 publications

References 38 publications

Aberrant JMJD3 Expression Upregulates Slug to Promote Migration, Invasion, and Stem Cell–Like Behaviors in Hepatocellular Carcinoma

Aberrant JMJD3 Expression Upregulates Slug to Promote Migration, Invasion, and Stem Cell–Like Behaviors in Hepatocellular Carcinoma

The Adult Ventricular–Subventricular Zone (V-SVZ) and Olfactory Bulb (OB) Neurogenesis

RIT1 GTPase Regulates Sox2 Transcriptional Activity and Hippocampal Neurogenesis

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