Involvement of Histone Demethylase LSD1 in Short-Time-Scale Gene Expression Changes during Cell Cycle Progression in Embryonic Stem Cells

Department of Neurology, Mount Sinai School of Medicine, New York, New York, USA.
Molecular and Cellular Biology (Impact Factor: 4.78). 10/2012; 32(23). DOI: 10.1128/MCB.00816-12
Source: PubMed


The histone demethylase LSD1, a component of the CoREST (corepressor for element 1-silencing transcription factor) corepressor
complex, plays an important role in the downregulation of gene expression during development. However, the activities of LSD1
in mediating short-time-scale gene expression changes have not been well understood. To reveal the mechanisms underlying these
two distinct functions of LSD1, we performed genome-wide mapping and cellular localization studies of LSD1 and its dimethylated
histone 3 lysine 4 (substrate H3K4me2) in mouse embryonic stem cells (ES cells). Our results showed an extensive overlap between
the LSD1 and H3K4me2 genomic regions and a correlation between the genomic levels of LSD1/H3K4me2 and gene expression, including
many highly expressed ES cell genes. LSD1 is recruited to the chromatin of cells in the G1/S/G2 phases and is displaced from the chromatin of M-phase cells, suggesting that LSD1 or H3K4me2 alternatively occupies LSD1
genomic regions during cell cycle progression. LSD1 knockdown by RNA interference or its displacement from the chromatin by
antineoplastic agents caused an increase in the levels of a subset of LSD1 target genes. Taken together, these results suggest
that cell cycle-dependent association and dissociation of LSD1 with chromatin mediates short-time-scale gene expression changes
during embryonic stem cell cycle progression.

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    • "We then studied the role of endogenous miR-137 in repressing the Klf4, Tbx3 and LSD1 3′UTR reporters in wild type ES cells (R1) under self-renewal conditions (Nair et al., 2012). At 48 h after transfection, there was a small but significant repression of the wild-type 3′UTR luciferase reporter activities of Klf4, Tbx3, and LSD1 in comparison to the no-UTR control (Figs. "
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    ABSTRACT: MicroRNA-137 (miR-137) has been shown to play an important role in the differentiation of neural stem cells. Embryonic stem (ES) cells have the potential to differentiate into different cell types including neurons; however, the contribution of miR-137 in the maintenance and differentiation of ES cells remains unknown. Here, we show that miR-137 is mainly expressed in ES cells at the mitotic phase of the cell cycle and highly upregulated during differentiation. We identify that ES cell transcription factors, Klf4 and Tbx3, are downstream targets of miR-137, and we show that endogenous miR-137 represses the 3' untranslated regions of Klf4 and Tbx3. Transfection of ES cells with mature miR-137 RNA duplexes led to a significant reduction in cell proliferation and the expression of Klf4, Tbx3, and other self-renewal genes. Furthermore, we demonstrate that increased miR-137 expression accelerates differentiation of ES cells in vitro. Loss of miR-137 during ES cell differentiation significantly impeded neuronal gene expression and morphogenesis. Taken together, our results suggest that miR-137 regulates ES cell proliferation and differentiation by repressing the expression of downstream targets, including Klf4 and Tbx3.
    Stem Cell Research 09/2013; 11(3):1299-1313. DOI:10.1016/j.scr.2013.09.001 · 3.69 Impact Factor
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    ABSTRACT: Abstract The flavin adenine dinucleotide-dependent amine oxidase LSD1 is the first molecularly defined histone demethylase, which specifically demethylates H3K4me1/me2. The enzyme dynamically controls a large variety of biological processes and is associated with protein complexes controlling transcriptional repression and activation. Molecular analysis of the Drosophila LSD1 homolog revealed new insights into epigenetic control of heterochromatin formation during early embryogenesis, the establishment of transcriptional gene silencing and the epigenetic mechanisms associated with maintenance of stem cell identity in primordial germline cells. This review summarizes our recent knowledge about control of enzymatic activity and molecular function of LSD1 enzyme complexes in different model organisms including Schizosaccharomyces pombe, Drosophila and mammals. Finally, new developments in applied cancer research based on molecular analysis of LSD1 in cancer cells are discussed.
    Biological Chemistry 03/2013; 394(8). DOI:10.1515/hsz-2013-0119 · 3.27 Impact Factor
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    ABSTRACT: Genome-wide maps of DNase I hypersensitive sites (DHSs) reveal that most human promoters contain perpetually active cis-regulatory elements between -150 bp and +50 bp (-150/+50 bp) relative to the transcription start site (TSS). Transcription factors (TFs) recruit cofactors (chromatin remodelers, histone/protein-modifying enzymes, and scaffold proteins) to these elements in order to organize the local chromatin structure and coordinate the balance of post-translational modifications nearby, contributing to the overall regulation of transcription. However, the rules of TF-mediated cofactor recruitment to the -150/+50 bp promoter regions remain poorly understood. Here, we provide evidence for a general model in which a series of cis-regulatory elements (here termed 'cardinal' motifs) prefer acting individually, rather than in fixed combinations, within the -150/+50 bp regions to recruit TFs that dictate cofactor signatures distinctive of specific promoter subsets. Subsequently, human promoters can be subclassified based on the presence of cardinal elements and their associated cofactor signatures. In this study, furthermore, we have focused on promoters containing the nuclear respiratory factor 1 (NRF1) motif as the cardinal cis-regulatory element and have identified the pervasive association of NRF1 with the cofactor lysine-specific demethylase 1 (LSD1/KDM1A). This signature might be distinctive of promoters regulating nuclear-encoded mitochondrial and other particular genes in at least some cells. Together, we propose that decoding a signature-based, expanded model of control at proximal promoter regions should lead to a better understanding of coordinated regulation of gene transcription.
    PLoS Genetics 11/2013; 9(11):e1003906. DOI:10.1371/journal.pgen.1003906 · 7.53 Impact Factor
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