Alternative Splicing of G9a Regulates Neuronal Differentiation

Fiszbein, Ana; Giono, Luciana E.; Quaglino, Ana; Berardino, Bruno Gabriel; Sigaut, Lorena; Bilderling, Catalina von; Schor, Ignacio E.; Steinberg, Juliana Haydeé Enriqué; Rossi, Mario; Pietrasanta, Lı́a I.; Caramelo, Julio J.; Srebrow, Anabella; Kornblihtt, Alberto R.

doi:10.1016/j.celrep.2016.02.063

Cited by 71 publications

(69 citation statements)

References 62 publications

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“…Multiple splice variants have been noted both in the human and mouse, denoted by inclusion/exclusion of a 5 0 exon, as well as inclusion/exclusion of exon 10. [53][54][55][56] Although none of these splice variants has been reported to effect the overall HMT function of the Ehmt1/2 dimer, both alternatively spliced 5 0 domain and exon 10 have independently been reported to be required for nuclear localization. 54,56 Furthermore, activation by the human EHMT2 protein has been found to be predominantly dependent of the hEHMT2-s variant which lacks part of the 5 0 TAD, in at least some contexts.…”

Section: Methylation-independent Transcriptional Activating Functionsmentioning

confidence: 99%

“…[53][54][55][56] Although none of these splice variants has been reported to effect the overall HMT function of the Ehmt1/2 dimer, both alternatively spliced 5 0 domain and exon 10 have independently been reported to be required for nuclear localization. 54,56 Furthermore, activation by the human EHMT2 protein has been found to be predominantly dependent of the hEHMT2-s variant which lacks part of the 5 0 TAD, in at least some contexts. 53 It is therefore possible that alternative splicing the Ehmt2 transcript acts to balance both activator and repressor, as well as nuclear versus cytoplasmic functions.…”

Section: Methylation-independent Transcriptional Activating Functionsmentioning

confidence: 99%

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The expanding role of the Ehmt2/G9a complex in neurodevelopment

2017

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Epigenetic regulators play a crucial role in neurodevelopment. One such epigenetic complex, Ehmt1/2 (G9a/GLP), is essential for repressing gene transcription by methylating H3K9 in a highly tissue-and temporal-specific manner. Recently, data has emerged suggesting that this complex plays additional roles in regulating the activity of numerous other non-histone proteins. While much is known about the downstream effects of Ehmt1/2 function, evidence is only beginning to come to light suggesting the control of Ehmt1/2 function may be, at least in part, due to context-dependent binding partners. Here we review emerging roles for the Ehmt1/2 complex suggesting that it may play a much larger role than previously recognized, and discuss binding partners that we and others have recently characterized which act to coordinate its activity during early neurodevelopment.

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Section: Methylation-independent Transcriptional Activating Functionsmentioning

confidence: 99%

Section: Methylation-independent Transcriptional Activating Functionsmentioning

confidence: 99%

The expanding role of the Ehmt2/G9a complex in neurodevelopment

2017

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“…JHDMs, which belong to the superfamily of 2-oxoglutarate and Fe 2+ -dependent dioxygenases, hydroxylate the methyl group in a lysine residue of histones, and in turn the oxidized methyl is released as formaldehyde (50) not been demonstrated, it was reported that substantial amounts of G9a and its splicing variant are present in the cytoplasm (52). In addition, a proteomic analysis revealed that many non-histone proteins in the cytoplasm are methylated by G9a/GLP (53), which indirectly supports the cytoplasmic location of G9a/GLP.…”

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confidence: 99%

FIH Is an Oxygen Sensor in Ovarian Cancer for G9a/GLP-Driven Epigenetic Regulation of Metastasis-Related Genes

et al. 2018

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The prolyl hydroxlyases PHD1-3 and the asparaginly hydroxlyase FIH are oxygen sensors for HIF-driven transcription of hypoxia-induced genes, but whether these sensors affect oxygendependent epigenetic regulation more broadly is not known. Here we show that FIH exerts an additional role as an oxygen sensor in epigenetic control by the histone lysine methyltransferases G9a and GLP. FIH hydroxylated and inhibited G9a and GLP under normoxia. When the FIH reaction was limited under hypoxia, G9a and GLP were activated and repressed metastasis suppressor genes, thereby triggering cancer cell migration and peritoneal dissemination of ovarian cancer xenografts. In clinical specimens of ovarian cancer, expression of FIH and G9a were reciprocally associated with patient outcomes. We also identified mutations of FIH target motifs in G9a and GLP, which exhibited excessive H3K9 methylation and facilitated cell invasion. This study provides insight into a new function of FIH as an upstream regulator of oxygen-dependent chromatin remodeling. It also implies that the FIH-G9a/GLP pathway could be a potential target for inhibiting hypoxiainduced cancer metastasis.

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“…Interestingly, another histone methyl transferase, G9a, that is specific for dimethylation of H3K9 has recently been shown to participate in an alternative splicing positive loop that enhances neuron differentiation (18). It is now more evident that when studying the molecular bases of cancer, the view should not be restricted to transcriptional regulation or to epigenetic alterations at the promoter and regulatory regions of genes.…”

Section: Discussionmentioning

confidence: 99%

Epigenetics at the base of alternative splicing changes that promote colorectal cancer

Kornblihtt¹

2017

Journal of Clinical Investigation

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Human genes, as well as those of most multicellular eukaryotes, are organized as mosaics of exons and introns. RNA polymerase II (RNAPII) transcribes the DNA sequence of each gene to generate a precursor mRNA molecule (pre-mRNA) that contains both exons and introns and serves as the substrate for splicing, the process by which introns are removed and exons are joined, yielding the mature mRNA that will eventually be translated to protein.One of the evolutionary advantages of premRNA splicing is the ability to alter mature mRNA via alternative splicing, which allows generation of multiple mRNA and protein variants from each gene, thereby greatly expanding the coding capacity of the genome. Indeed, the number of proteincoding genes in humans is not radically different from that in the worm Caenorhabditis elegans (~20,000). However, alternative splicing is prevalent in vertebrates (1), strongly suggesting a key role in the higher complexity of these organisms. As a compelling example, alternative splicing occurs in more than 95% of mammalian genes (2). In alternative splicing, a single type of pre-mRNA can be spliced in different ways, leading to similar but not identical mature mRNA species. A simple metaphor is that of a textile industry (transcription) that generates many copies of a fabric piece of the same length and quality (pre-mRNAs) and the tailor (the spliceosome) who makes different suits (mRNAs) with each piece of fabric, depending on where he/she cuts and sews (splicing) and on the remnants (introns) that are discarded.Splicing is carried out by the spliceosome, a multimolecular complex composed of dozens of proteins and ribonucleoproteins. A single spliceosome assembles at every intron to be excised on each premRNA as soon as it emerges from RNAPII during transcription (3). Indeed, accumulating evidence indicates that splicing, or at least the binding of spliceosome and splicing factors to the pre-mRNA that enables it, occurs cotranscriptionally (4). In turn, this cotranscriptionality allows for a complex molecular interplay between the transcription and splicing machineries so that both processes are mutually coordinated and the kinetics and molecular mechanisms intrinsic to each of them influence each other. As a consequence of this coupling, splicing, like transcription, is highly regulated by chromatin structure and the quality and distribution of posttranslational histone modifications (histone marks). Two modelsTwo nonmutually exclusive models have been proposed for the role of chromatin in alternative splicing. In the transcription kinetics model, the preferential positioning of nucleosomes in exons (5, 6) or deployment of specific histone marks within the gene body hinder or facilitate RNAPII progression. Changes in overall elongation rates of RNAPII have been shown to promote or inhibit the inclusion of alternative exons in the mature mRNA, depending on the identity of the particular alternative splicing event (7-9). Intragenic histone modifications, including H2B monoubiquitylation (10), H3K...

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Alternative Splicing of G9a Regulates Neuronal Differentiation

Cited by 71 publications

References 62 publications

The expanding role of the Ehmt2/G9a complex in neurodevelopment

The expanding role of the Ehmt2/G9a complex in neurodevelopment

FIH Is an Oxygen Sensor in Ovarian Cancer for G9a/GLP-Driven Epigenetic Regulation of Metastasis-Related Genes

Epigenetics at the base of alternative splicing changes that promote colorectal cancer

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