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Epigenetics & Chromatin 2015, 8:3 doi:10.1186/1756-8935-8-3
The electronic version of this article is the complete one and can be found online at: http://www.epigeneticsandchromatin.com/content/8/1/3
Constitutive heterochromatin, mainly formed at the gene-poor regions of pericentromeres, is believed to ensure a condensed and transcriptionally inert chromatin conformation. Pericentromeres consist of repetitive tandem satellite repeats and are crucial chromosomal elements that are responsible for accurate chromosome segregation in mitosis. The repeat sequences are not conserved and can greatly vary between different organisms, suggesting that pericentromeric functions might be controlled epigenetically. In this review, we will discuss how constitutive heterochromatin is formed and maintained at pericentromeres in order to ensure their integrity. We will describe the biogenesis and the function of main epigenetic pathways that are involved and how they are interconnected. Interestingly, recent findings suggest that alternative pathways could substitute for well-established pathways when disrupted, suggesting that constitutive heterochromatin harbors much more plasticity than previously assumed. In addition, despite of the heterochromatic nature of pericentromeres, there is increasing evidence for active and regulated transcription at these loci, in a multitude of organisms and under various biological contexts. Thus, in the second part of this review, we will address this relatively new aspect and discuss putative functions of pericentromeric expression.
N6- methyladenine; RNA demethylase; RNA epigenetics; reversible RNA methylation
DNA methylation has been recognized as a key mechanism in cell differentiation. Various studies have compared tissues to characterize epigenetically regulated genomic regions, but due to differences in study design and focus there still is no consensus as to the annotation of genomic regions predominantly involved in tissue-specific methylation. We used a new algorithm to identify and annotate tissue-specific differentially methylated regions (tDMRs) from Illumina 450k chip data for four peripheral tissues (blood, saliva, buccal swabs and hair follicles) and six internal tissues (liver, muscle, pancreas, subcutaneous fat, omentum and spleen with matched blood samples).
The majority of tDMRs, in both relative and absolute terms, occurred in CpG-poor regions. Further analysis revealed that these regions were associated with alternative transcription events (alternative first exons, mutually exclusive exons and cassette exons). Only a minority of tDMRs mapped to gene-body CpG islands (13%) or CpG islands shores (25%) suggesting a less prominent role for these regions than indicated previously. Implementation of ENCODE annotations showed enrichment of tDMRs in DNase hypersensitive sites and transcription factor binding sites. Despite the predominance of tissue differences, inter-individual differences in DNA methylation in internal tissues were correlated with those for blood for a subset of CpG sites in a locus- and tissue-specific manner.
We conclude that tDMRs preferentially occur in CpG-poor regions and are associated with alternative transcription. Furthermore, our data suggest the utility of creating an atlas cataloguing variably methylated regions in internal tissues that correlate to DNA methylation measured in easy accessible peripheral tissues.
Histone post-translational modifications (PTMs) have been linked to a variety of biological processes and disease states, thus making their characterization a critical field of study. In the last 5 years, a number of novel sites and types of modifications have been discovered, greatly expanding the histone code. Mass spectrometric methods are essential for finding and validating histone PTMs. Additionally, novel proteomic, genomic and chemical biology tools have been developed to probe PTM function. In this snapshot review, proteomic tools for PTM identification and characterization will be discussed and an overview of PTMs found in the last 5 years will be provided.
1] Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, Department of Obstetrics and Gynecology and Center for Reproductive Sciences, University of California San Francisco, 35 Medical Center Way, San Francisco, California 94143, USA .
DNA methylation is a heritable epigenetic modification involved in gene silencing, imprinting, and the suppression of retrotransposons. Global DNA demethylation occurs in the early embryo and the germ line, and may be mediated by Tet (ten?eleven?translocation) enzymes, which convert 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC). Tet enzymes have been studied extensively in mouse embryonic stem (ES) cells, which are generally cultured in the absence of vitamin?C, a potential cofactor for Fe(ii) 2-oxoglutarate dioxygenase enzymes such as Tet enzymes. Here we report that addition of vitamin?C to mouse ES cells promotes Tet activity, leading to a rapid and global increase in 5hmC. This is followed by DNA demethylation of many gene promoters and upregulation of demethylated germline genes. Tet1 binding is enriched near the transcription start site of genes affected by vitamin?C treatment. Importantly, vitamin?C, but not other antioxidants, enhances the activity of recombinant Tet1 in a biochemical assay, and the vitamin-C-induced changes in 5hmC and 5mC are entirely suppressed in Tet1 and Tet2 double knockout ES cells. Vitamin?C has a stronger effect on regions that gain methylation in cultured ES cells compared to blastocysts, and in vivo are methylated only after implantation. In contrast, imprinted regions and intracisternal A particle retroelements, which are resistant to demethylation in the early embryo, are resistant to vitamin-C-induced DNA demethylation. Collectively, the results of this study establish vitamin?C as a direct regulator of Tet activity and DNA methylation fidelity in ES cells.
Epigenetics & Chromatin 2013, 6:19
Smchd1 regulates a subset of autosomal genes
subject to monoallelic expression in addition to
being critical for X inactivation
Arne W Mould1,2, Zhenyi Pang1, Miha Pakusch3, Ian D Tonks1, Mitchell Stark1, Dianne Carrie1,
Pamela Mukhopadhyay1, Annica Seidel1, Jonathan J Ellis1, Janine Deakin4, Matthew J Wakefield3,5, Lutz Krause1,
Marnie E Blewitt3,5,6 and Graham F Kay1*
Background: Smchd1 is an epigenetic modifier essential for X chromosome inactivation: female embryos lacking
Smchd1 fail during midgestational development. Male mice are less affected by Smchd1-loss, with some (but not
all) surviving to become fertile adults on the FVB/n genetic background. On other genetic backgrounds, all males
lacking Smchd1 die perinatally. This suggests that, in addition to being critical for X inactivation, Smchd1 functions
to control the expression of essential autosomal genes.Results: Using genome-wide microarray expression profiling and RNA-seq, we have identified additional genes that
fail X inactivation in female Smchd1 mutants and have identified autosomal genes in male mice where the normal
expression pattern depends upon Smchd1. A subset of genes in the Snrpn imprinted gene cluster show an
epigenetic signature and biallelic expression consistent with loss of imprinting in the absence of Smchd1. In
addition, single nucleotide polymorphism analysis of expressed genes in the placenta shows that the Igf2r
imprinted gene cluster is also disrupted, with Slc22a3 showing biallelic expression in the absence of Smchd1.
In both cases, the disruption was not due to loss of the differential methylation that marks the imprint control
region, but affected genes remote from this primary imprint controlling element. The clustered protocadherins
(Pcdhα, Pcdhβ, and Pcdhγ) also show altered expression levels, suggesting that their unique pattern of random
combinatorial monoallelic expression might also be disrupted.Conclusions: Smchd1 has a role in the expression of several autosomal gene clusters that are subject to
monoallelic expression, rather than being restricted to functioning uniquely in X inactivation. Our findings,
combined with the recent report implicating heterozygous mutations of SMCHD1 as a causal factor in the
digenically inherited muscular weakness syndrome facioscapulohumeral muscular dystrophy-2, highlight the
potential importance of Smchd1 in the etiology of diverse human diseases.Keywords: Clustered protocadherins, Genomic imprinting, Monoallelic expression, Smchd1, X inactivation