Epigenetics & Chromatin


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    Epigenetics and chromatin
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Publications in this journal

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    ABSTRACT: Epigenetic modifications such as histone and DNA methylation are essential for silencing pluripotency genes during embryonic stem cell (ESC) differentiation. G9a is the major histone H3 Lys9 (H3K9) methyltransferase in euchromatin and is required for the de novo DNA methylation of the key regulator of pluripotency Oct3/4 during ESC differentiation. Surprisingly, the catalytic activity of G9a is not required for its role in de novo DNA methylation and the precise molecular mechanisms of G9a in this process are poorly understood. It has been suggested that the G9a ankyrin repeat domain, which can interact with both H3K9me2 and the DNA methyltransferase DNMT3A, could facilitate de novo DNA methylation by bridging the interaction between DNMT3A and H3K9me2-marked chromatin. Here, we demonstrate that the G9a ankyrin domain H3K9me2-binding function is not required for the de novo DNA methylation of Oct3/4 during ESC differentiation. Moreover, we show that the interaction between the G9a ankyrin domain and DNMT3A is not sufficient to ensure efficient de novo DNA methylation. More importantly, we characterize a specific residue of the G9a ankyrin domain (Asp905) that is critical for both maintaining cellular H3K9me2 levels in undifferentiated ESCs and for the establishment of de novo DNA methylation during differentiation. These results represent an exciting breakthrough, which reveals 1) an unexpected critical biological function of the G9a ankyrin domain in global histone H3K9 methylation and 2) valuable insights into the molecular mechanisms and interaction surfaces through which G9a regulates de novo DNA methylation of Oct3/4 during ESC differentiation.
    Epigenetics & Chromatin 01/2014; 7:27.
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    ABSTRACT: DNA methylation is thought to play an important role in the regulation of mammalian gene expression, partly based on the observation that a lack of CpG island methylation in gene promoters is associated with high transcriptional activity. However, the CpG island methylation level only accounts for a fraction of the variance in gene expression, and methylation in other domains is hypothesized to play a role. We hypothesized that regions of very high stability in methylation would exist and provide biological insight into the role of methylation both within and outside CpG islands. We set out to identify highly stable regions in the human methylome, based on the subset of CpGs assayed with an Illumina Infinium 450 K array. Using 1,737 samples from 30 publically available studies, we identified 15,224 CpGs that are 'ultrastable' in their state across tissues and developmental stages (974 always methylated; 14,250 always unmethylated). Further analysis of ultrastable CpGs led us to identify a novel subset of CpG islands, 'ravines', which exhibit a markedly consistent pattern of low methylation with highly methylated flanking shores and shelves. We distinguish ravines from other CpG islands characterized by a broader flanking region of low methylation. Interestingly, ravines are associated with higher gene expression compared to typical unmethylated CpG islands, and are more often found near housekeeping genes. The identification of ultrastable sites in the human methylome led us to identify a subclass of CpG islands characterized by a very stable pattern of methylation encompassing the island and flanking regions, established early in development and maintained through differentiation. This pattern is associated with particularly high levels of gene expression, providing new evidence that methylation beyond the CpG island could play a role in gene expression.
    Epigenetics & Chromatin 01/2014; 7(1):28.
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    ABSTRACT: Stored, soluble histones in eggs are essential for early development, in particular during the maternally controlled early cell cycles in the absence of transcription. Histone post-translational modifications (PTMs) direct and regulate chromatin-templated transactions, so understanding the nature and function of pre-deposition maternal histones is essential to deciphering mechanisms of regulation of development, chromatin assembly, and transcription. Little is known about histone H2A pre-deposition modifications nor known about the transitions that occur upon the onset of zygotic control of the cell cycle and transcription at the mid-blastula transition (MBT).
    Epigenetics & Chromatin 01/2014; 7:22.
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    ABSTRACT: Transcriptional activation throughout the eukaryotic lineage has been tightly linked with disruption of nucleosome organization at promoters, enhancers, silencers, insulators and locus control regions due to transcription factor binding. Regulatory DNA thus coincides with open or accessible genomic sites of remodeled chromatin. Current chromatin accessibility assays are used to separate the genome by enzymatic or chemical means and isolate either the accessible or protected locations. The isolated DNA is then quantified using a next-generation sequencing platform. Wide application of these assays has recently focused on the identification of the instrumental epigenetic changes responsible for differential gene expression, cell proliferation, functional diversification and disease development. Here we discuss the limitations and advantages of current genome-wide chromatin accessibility assays with especial attention on experimental precautions and sequence data analysis. We conclude with our perspective on future improvements necessary for moving the field of chromatin profiling forward.
    Epigenetics & Chromatin 01/2014; 7(1):33.
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    ABSTRACT: The formation of chromatin domains is an important step in lineage commitment. In human hematopoietic stem and progenitor cells (HSPCs), G9a/GLP-dependent H3K9me2 chromatin territories form de novo during lineage specification and are nucleated at punctate sites during lineage commitment. Here, we examined the patterning of G9a/GLP-dependent H3K9me2 in HSPCs and the consequences for chromatin structure.
    Epigenetics & Chromatin 01/2014; 7:23.
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    ABSTRACT: X chromosome inactivation (XCI) is a developmental program of heterochromatin formation that initiates during early female mammalian embryonic development and is maintained through a lifetime of cell divisions in somatic cells. Despite identification of the crucial long non-coding RNA Xist and involvement of specific chromatin modifiers in the establishment and maintenance of the heterochromatin of the inactive X chromosome (Xi), interference with known pathways only partially reactivates the Xi once silencing has been established. Here, we studied ATF7IP (MCAF1), a protein previously characterized to coordinate DNA methylation and histone H3K9 methylation through interactions with the methyl-DNA binding protein MBD1 and the histone H3K9 methyltransferase SETDB1, as a candidate maintenance factor of the Xi.
    Epigenetics & Chromatin 01/2014; 7:12.