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    • Once committed to a certain cell

    2018-10-20

    Once committed to a certain cell fate, NPC undergo cell cycle arrest and terminal differentiation leading to the exhibition of cell-type-specific features. The onset and processes of neuronal and astroglial differentiation involve extensive chromatin remodeling and precise regulation of transcription (Hirabayashi and Gotoh, 2010). Epigenetic enzymes including epigenetic writers and erasers, and small molecules that can target some of the enzymes have been demonstrated to induce the alternations of a large array of gene expression and the modulation of multiple neural development pathways during these processes (Swaminathan et al., 2014). HDAC inhibitors such as valproic Rupatadine Fumarate (VPA) were found to induce neuronal differentiation of NPC, whereas it inhibited astrocyte and oligodendrocyte differentiation. VPA treatment upregulated proneurogenic genes NeuroD and Neurogenins (Ngn) through promoting recruiting Actylated-H4 to their promoters for transcriptional activation (Hsieh et al., 2004; Yu et al., 2009). BET proteins as epigenetic readers bind acetylated histones and are a crucial regulator of transcription in many cell types. Brd4, a well-studied member of the BET family, was found to recruit transcriptional regulatory complexes including P-TEFb and Mediators to acetylated chromatin thereby coupling the acetylation state of chromatin with Pol II elongation. Interestingly, global transcriptomic analyses on the effects of BET bromodomain inhibitors revealed that the transcriptional effects of BET inhibitors are often highly specific to the cell type and/or the physiology and pathophysiology process being examined (Shi and Vakoc, 2014). For example, treating macrophage cells with I-BET prevented the activation of a specific subset of LPS-inducible genes that encode cytokines, chemokines and various transcription factors involved in the inflammatory response. In the absence of LPS stimulation, I-BET treatment led to minimal changes to global gene expression in macrophages, indicating selective effects of BET inhibitors on inflammatory genes in this cell type (Nicodeme et al., 2010). In NPC among the genes regulated by (+)-JQ-1, biological process and pathway analyses revealed that bromodomain inhibition leads to the most significant changes in NSC lineage commitment, the differentiation of oligodendrocytes and astrocytes, neurogenesis, and the processes and signaling pathways associated with NPC development. A significantly large number of genes were downregulated, which are likely to be the direct and secondary targets of BETs as a result of their function as transcriptional activators (Shi and Vakoc, 2014). Both astroglial and oligodendroglial differentiation pathways were significantly perturbed in response to (+)-JQ-1 treatment, and the expression of their downstream target genes were markedly suppressed. Bone morphogenetic proteins (BMPs) are known to promote glial differentiation and inhibit neuronal fate specification (Bonaguidi et al., 2005; Lim et al., 2000). BMPs mainly potentiate JAK/STAT signaling through the formation of a STAT-SMAD co-activating complex (Faigle and Song, 2013). Platelet-derived growth factor (PDGF) is not only a mitogen for the proliferation of oligodendrocyte progenitor cells, but also an instructional signal for the differentiation of neural stem cells into oligodendrocyte lineage (Fruttiger et al., 1999; Hu et al., 2008). During the neurogenic phase of NPC development, suppression of alternative fates while promotion of neurogenesis are known mechanisms for neuronal fate specification (Sun et al., 2001). (+)-JQ-1 induced suppression of transcriptions on these lineage specification signals (for example BMP and PDGF) and downstream genes towards the differentiation and maturation of astrocyte and oligodendrocyte might directly contribute to the inhibition of gliogenesis and promotion of neuronal differentiation. Moreover, (+)-JQ1 treatment induced increased gene expression involved in chromatin assembly, epigenetic regulation and neurogenesis. Distal-less homeobox 2 (Dlx2) is a helix-loop-helix transcription factor that is heavily controlled by epigenetic modifications (Lim et al., 2009). Over-expression of Dlx2 is required for GABAergic neuron production. It negatively regulates Oligo2-dependent oligodendrocyte formation (Brill et al., 2008; Petryniak et al., 2007; Suh et al., 2009). Bcl6, an oncogene in B lymphocytes encoding a BTB/POZ zinc finger transcription repressor, was recently identified as a proneurogenic gene necessary for proper cortical neurogenesis and pyramidal neuron differentiation through selective regulation of Notch-dependent transcription (Tiberi et al., 2012). The “cell cycle length hypothesis”, in vitro and in vivo studies suggested that inhibition of the cell cycle favors neurogenesis and prevents proliferation of NPCs (Arai et al., 2011; Gotz and Huttner, 2005; Knoepfler et al., 2002). Consistent with this hypothesis, accompanied with increased neuronal differentiation, the transcriptions of Cdkn1C, CyclinD1, Myc and MycN genes that are involved in cell cycle progression were markedly suppressed by (+)-JQ-1 treatment. The genome-wide analysis of Brd4 chromatin occupancy using chromatin immunoprecipitation coupled with DNA sequencing (CHIP-Seq) showed that Brd4 is associated with essentially all active promoters and a significant fraction of active enhancers in the genome of various normal and transformed cell types (Anand et al., 2013; Loven et al., 2013). Examination of Brd4 occupancy at genes whose transcription is particularly sensitive to (+)-JQ-1 has led to the observation that such genes often exhibit high levels of Brd4 occupancy at nearby super enhancer regions. The association of high-level of Brd4 occupancy with these lineage-specific enhancers has been linked to the lineage-specific gene regulation by BET inhibition (Shi and Vakoc, 2014). Future study on CHIP-seq analysis of (+)-JQ-1 treated differentiating NPC might be able to identify these enhancer elements that are selectively targeted by BET inhibition and underlie the effects of I-BET in NPC development.