All tags epigenetics Top Epigenetics articles: May 2015

Top Epigenetics articles: May 2015

Looking for an easy way to keep on top of the latest Epigenetics literature? Sit back and read our top picks from May.


Experience-dependent DNA methylation regulates plasticity in the developing visual cortex

Monocular deprivation regulates DNA methylation in the visual cortex

Changes to DNA methylation are involved in learning and synaptic plasticity in the brain. However, the role of DNA methylation in experience-dependent plasticity during development is unclear.

To further understand visual experience regulation of DNA methylation, a team led by Tommaso Pizzorusso from the Institute of Neuroscience CNR in Pisa studied the role of DNA methylation in ocular dominance plasticity in the developing visual cortex of mice. They found that:

  • Monocular deprivation led to increased DNA methylation on the promoters of plasticity genes miR-132 and BDNFex4 in the contralateral cortex, but resulted in a significant decrease in 5-hmC.
  • DNA methyltransferase (DNMT) inhibition lessened downregulation of these genes in monocular deprived mice.
  • Genome-wide analysis of the effect of DNMT inhibition showed a reversal of a substantial fraction of the transcriptional program induced by monocular deprivation.

The data presented in this paper show that monocular deprivation regulates DNA methylation at specific loci in the visual cortex. This might highlight a wider role of DNA methylation as a mediator of experience-dependent refinement of cortical circuits during development.

Read the full text in Nature Neuroscience, May 2015.



Dissecting the role of abberant DNA methylation in human leukaemia

DNA methylation is required for the oncogenic potential of BCR-ABR

Chronic myeloid leukemia (CML) is characterized by the presence of the BCR-ABL oncogene, a constituative active tyrosine kinase that mediates proliferation and differentiation pathways. Other molecular mechanisms contributing to CML onset have not previously been determined; however, epigenetic changes have recently been suggested to have an important role in leukemia pathogenesis.

A team led by Daniel Tenen from Harvard Medical School and the National University of Singapore sought to understand the functional relevance of aberrant DNA methylation in the development of CML. By reprogramming CML cells to an iPS-like state, followed by in vitro re-differentiation, the authors found that:

  • Although CML cells have widespread hypermethylation, the leukemia-specific methylation pattern is erased in leukemia cells that have been reprogrammed to an iPS-like state (LiPS cells).
  • Of the five hundred strongest differentially methylated regions associated with gene promoters, most are hypermethylated in CML cells compared with LiPS cells and associated with development, differentiation and signaling.
  • LiPS clone-derived CD45+CD15+ cells display typical monocyte and macrophage morpholgy and have reduced malignancy when transplanted into mice.
  • Activation of BCR-ABL in murine hematopoietic stem cells induces aberrant DNA methylation, and subsequent repression of BCR-ABL reverses these DNA methylation changes.
  • Inhibition of DNA methylation with 5-azacytidine reduces the oncogenic potential of BCR-ABL-expressing cells.

These data highlight the importance of DNA methylation in CML and indicate that DNA methylation is required for the oncogenic potential of BCR-ABR. This study opens up the potential for testing demethylating agents as a treatment strategy for CML.

Read the full paper at Nature Communications, May 2015

For more information on DNA methylation, view our DNA methylation articles, webinars and protocols.



An epigenetic memory of pregnancy in the mouse mammary gland

A role for DNA methylation in epigenetic memory of pregnancy

During pregnancy, a large expansion of the mammary epithelium and developing ductal structures occurs to support milk production. Anecdotal evidence suggests that the response of mammary glands to pregnancy is stronger after the first pregnancy, indicating a long term memory of the pregnancy.

To confirm this, and elucidate the molecular mechanisms responsible, Camila dos Santos and colleagues from Cold Spring Harbor Laboratory and the University of Southern California compared genome-wide DNA methylation profiles in mammary cells of post-pubescence and post-pregnancy mice.

They found that:

  • Exposing mice to pregnancy-associated hormones resulted in a greater and earlier response in terms of ductal branching morphogenesis and milk production in post-pregnancy mice than mice that had never been pregnant.
  • DNA methylomes were significantly different in mammary cell types post-pregnancy compared with pre-pregnancy.
  • Differentially methylated regions were strongly enriched for motifs recognized by the STAT5 transcription factor, suggesting that STAT5 activity during pregnancy has a role related to the acquisition of the hypomethylated state retained after pregnancy.
  • The vast majority of hypomethylated regions persisted throughout the mouse reproductive life span, and genes with pregnancy-associated hypomethylated regions showed a greater transcriptional response upon treatment with pregnancy-associated hormones.

The authors postulate that the epigenetic memory of a first pregnancy primes the activation of gene expression networks that promote mammary gland function in subsequent reproductive cycles.

Read the full paper at Cell Reports, May 2015



Gender-specific postnatal demethylation and establishment of epigenetic memory

DNA methylation has a role in regulating gender-specific gene expression

Male and female genomes differ in only their X and Y chromosomes, and little is understood about how changes in the expression of autosomal genes arise.

To understand whether DNA methylation has a role in gender-specific gene expression, a team led by Howard Cedar from Cedars-Sinai Medical Center in California undertook a high-throughput analysis to characterize DNA methylation differences between males and females. Here is what they found:

  • Reduced representation bisulfite sequencing was able to identify 160 individual regions that were at least 25% less methylated in male compared with female samples.
  • Male mice castrated at 20 d did not undergo demethylation during postnatal development, whilst testosterone administration into these mice restored demethylation pattern. This suggests a role for male hormones in determining DNA methylation.
  • Regions that undergo demethylation are enriched for enhancer elements, and demethylation is strongly correlated to gender-specific gene expression.
  • In adult human liver samples, 450 regions are significantly demethylated in males compared with females, in regions that are characteristic of enhancer elements.

This paper presents an example of how DNA methylation changes brought on during development can be maintained and regulate gene expression in the adult. The authors suggest that methylation may play a general role in regulating male and female characteristics independent of sex determination.

Read the full paper at Genes and Development, May 2015.

Interested in DNA methylation in development? View our webinar on DNA methylation changes during cell differentiation with Esteban Ballestar.



RNA exosome-regulated long non-coding RNA transcription controls super-enhancer activity

Transcription of lncRNAs is required for super-enhancer chromosomal interactions

The RNA exosome complex is responsible for the degradation and processing of RNAs both in the nucleus and the cytosol. In this study, a team led by Uttiya Basu from Columbia University sought to elucidate the role of the RNA exosome in chromatin-associated events.

By looking at the transcriptomes of embryonic stem cells (ESCs) and B cells in which core components of the RNA exosome were ablated, they found that:

  • There is a significant increase in relative levels of lncRNAs, antisense RNAs and enhancer RNAs (eRNAs) in transcriptomes of exosome-deficient cells.
  • A subset of eRNAs acts as a target for the RNA exosomes in ESCs and B cells.
  • RNA exosome-deficient cells display genomic instability, accumulation of DNA/RNA hybrid regions and loss of DNA methylation marks.
  • Super-enhancers are controlled by the expression or processing of RNA exosome substrate non-coding RNAs.
  • An RNA expressing element termed lncRNA-CSR engages in long-range DNA interactions and regulates super-enhancer function.
  • Ablation of lncRNA-CSR decreases its interaction with the IgH 3' regulatory region super enhancer.

The authors propose that super-enhancers regulate genes through interactions dependent on the transcription of RNA exosome-substrate transcripts. The data suggest that the RNA exosome may resolve deleterious secondary DNA structures, to protect lncRNA expressing enhancers and regulate super-enhancer chromosomal interactions.

Read the full paper at Cell, May 2015.

Find out more with our guide to non-coding RNAs.



Histone H3.3 is required for endogenous retroviral element silencing in embryonic stem cells

A role for H3.3 in transposable element silencing

Transposable elements play a role in genetic variation, adaptation and evolution. Hosts have evolved the ability to silence transposable elements to prevent genome instability caused by transposable element activity, with H3K9 trimethylation known to silence endogenous retroviral elements (ERVs) containing long terminal repeats.

While the histone variant H3.3 has traditionally been associated with gene activation, it has also been shown to be present in constitutive and facultative heterochromatin. Simon Elsässer, Laura Banaszynski and colleagues from the MCR Laboratory of Molecular Biology in Cambridge, Karolinska Institutet, Rockefeller University and the UT Southwestern Medical Center in Texas used ChIP-seq to understand if H3.3 plays a role in silencing of ERVs.

They found that:

  • H3.3 and H3K9me3 are enriched at ERV-associated chromatin in embryonic stem cells, but are lost upon differentiation.
  • The histone chaperone complex DAXX-ATRX is required for H3.3 deposition at a subset of ERVs.
  • H3.3, DAXX and the co-repressor KAP1 cooperate to silence ERVs.
  • Upon H3.3 loss, H3K9me3 is reduced at sites that would normally be enriched with H3.3 and H3K9me3, suggesting that H3.3 is required for H3K9me3 maintenance.
  • Loss of H3.3 leads to upregulation of genes in the vicinity of ERVs, signaling ERV depression.

In this paper, the authors have provided further evidence of the important role of H3.3 in establishing silenced chromatin. They propose a model in which H3.3-containing chromatin recruits KAP1 to ERVs, which in turn recruits DAXX-ATRX for the maintenance of H3.3.

Read the full paper in Nature, May 2015.

Need more information on histone modifications? Take a look at our histone modification guide.



Multiplex single-cell profiling of chromatin accessibility by combinatorial cellular indexing

A new technique to assess chromatin accessibility in individual cells

Chromatin state is heterogeneous within cell populations. However, methods to characterize the epigenome, such as DNase-seq and ATAC-seq, measure an average of chromatin states, thus masking this heterogeneity.

To gain data from thousands of single cells without requiring individual processing, a team led by Jay Shendure from the University of Washington applied combinatorial cellular indexing integrated with ATAC-seq to measure chromatin accessibility of single cells.

The new method involves:

  • Molecular tagging of nuclei with barcoded transposase complexes
  • Pooling, diluting and redistribution of nuclei in a 96 well plate using a cell sorter
  • Lysing of nuclei, followed by introduction of a second barcode during PCR with indexed promoters complementary to the transposase-introduced adapters
  • Pooling and sequencing of PCR products; it is expected that sequence reads bearing the same combination of barcodes will be derived from a single cell.

In this paper, the authors demonstrate that this method is suitable for clustering cells based on chromatin accessibility and identifying modules of coordinately regulated chromatin accessibility. The authors argue that the simplicity and scalability of this method could accelerate the characterization of complex tissues.

Read the full paper in Science, May 2015.

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