All tags epigenetics Epigenetics articles of the month: March 2016

Epigenetics articles of the month: March 2016

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

Cell-of-origin-specific 3D genome structure acquired during somatic cell reprogramming

Changes in genome topology accompany cell reprogramming

Overexpression of reprogramming factors drives somatic cells to become induced pluripotent stem cells (iPSCs). Although iPSCs are able to contribute to all tissues, there is evidence that the differentiation propensity of iPSCs reflects their tissue of origin.

To understand whether the 3D genome structure contributes to differentiation bias of in iPSCs, a team led by Thomas Graf from Pompeu Fabra University in Barcelona sought to understand how genome topology changes during reprogramming of somatic cells. They found the following:

    • Cell of origin influences gene expression in p3 passage iPSCs, but this effect is reduced in p20 iPSCs.
    • Genome folding differs between different somatic cell types; however, reprogramming erases many tissue-specific configurations and results in a 3D configuration that is similar between iPSC lines.
    • However, early passage iPSCs contain topological hallmarks specific to their cell of origin.

    Taken together, these data show that  changes in genome topology accompany cell reprogramming. Established pluripotent cells share the same topology regardless of their cell of origin, although early passage cells have some differences.

    Read the full paper in Cell Stem Cell, March 2016.


    DNA methylation on N6-adenine in mammalian embryonic stem cells

    Role of N6-methyladenine in epigenetic silencing

    DNA methylation is commonly thought to occur in mammals solely as 5-methylcytosine. Although existence of N6-methyladenine (N6-mA) in organisms such as insects, nematodes and green algae – where it has a gene activating role – its presence has not previously been confirmed in mammals.

    A team led by Andrew Xiao from Yale School of Medicine, Connecticut have uncovered evidence of N6-adenine modification in mammals. They found the following:

    • N6-mA sites are present in mammals in H2A.X-deposition regions.
    • Alkbh1 encodes an N6-mA demethylase. Knockout of this gene increases N6-mA levels and downregulates expression of 550 genes.
    • N6-mA deposition is strongly enriched at evolutionarily young, but not old, LINE-1 transposons.
    • Increasing N6-mA results in silencing of nearby genes.

    These results demonstrate that N6-mA has a role in epigenetic silencing in mammals, distinct from its gene activating role in other organisms.

    Read the full paper in Nature, March 2016.


    Heterogeneity in Oct4 and Sox2 targets biases cell fate in 4-cell mouse embryos

    Cell fate determination begins the four-cell stage

    Segregation of the trophectoderm (TE) and inner cell mass (ICM) occurs primarily as a result of asymmetric cell divisions in the pre-implantation embryo. However, it is still unknown when cells start to differ from each other in mammalian development, and whether the initial differences are important for subsequent cell fate.

    To understand how and when embryonic and extra-embryonic cell fates are established, a team led by Magdalena Zernicka-Goetz from the University of Cambridge, UK characterized individual cell transcriptomes during pre-implantation development. Here is what they found:

    • Oct4 and Sox2 are heterogeneously expressed in the four-cell embryo, resulting in heterogeneous expression of the Sox2 target, Sox21.
    • Cells with decreased Sox21 contribute more to extra-embryonic TE than to pluripotent ICM lineages.
    • Cells with reduced Sox21 are first to upregulate the differentiation regulator Cdx2, and are first to initiate development into the extra-embryonic lineage.
    • In the four-cell embryo, the histone H3R26 methylase, Carm1, controls pluripotency regulators including Sox21.

    These results indicate that cell fate is determined by heterogeneous expression of pluripotency factors from as early as the four-cell stage. 

    Read the full paper in Cell, March 2016.


    Long-lived binding of Sox2 to DNA predicts cell fate in the four-cell embryo

    Sox2 DNA-binding properties predict mammalian cell fate

    Transcription factors Oct4 and Sox2 are involved in the pluripotent cell lineage in the early mammalian embryo. However, as most cells express these transcription factors, it remains unknown how only some cells acquire a pluripotent state.

    To understand how transcription factor-DNA interactions change during cell fate determination in vivo, a team led by Nicolas Plachta from the Agency for Science, Technology and Research in Singapore investigated the DNA-bindnig dynamics of Oct4 and Sox2 in the developing mouse embryo. The found the following:

    • Transcription factors involved in pluripotent and extra-embryonic cells have lineage-specific DNA-binding properties.
    • At the four-cell stage, there is significant cell-to-cell variability in Sox2 binding to DNA, with a selective increase in the long-lived bound fraction in one cell of pair of sister blastomeres.
    • Carm1 and H3R26 regulate long-lived DNA binding of Sox2. Carm1 downregulation reduces H3R26 and reduces the long-lived bound fraction of Sox2.
    • Four-cell blastomeres with larger long-lived Sox2-bound fractions contribute significantly more to the inner cell mass.

    The results in this paper demonstrate that Sox2 DNA-binding properties predict mammalian cell fate at teh four-cell stage. The authors show that Sox2 DNA binding properties are driven by epigenetic changes.

    Read the full paper in Cell, March 2016​.


    UTX inhibition as selective epigenetic therapy against TAL-1-driven T-cell acute lymphoblastic leukemia 

    UTX is a coactivator of the TAL-1 transcriptional regulatory program

    UTX inhibition as selective epigenetic therapy against TAL1-driven T-cell acute lymphoblastic leukemia
    T cell acute lymphoblastic leukemias (T-ALLs) are aggressive hematological tumors that vary in their genetic abnormalities and prognoses. In particular, TAL1 positive T-ALLs have a poor prognosis compared with other types. TAL1 has been shown to control expression of genes necessary for cell growth and maintenance.
    To understand the molecular mechanism though which TAL1 regulates transcription of its target genes, team led by Marjorie Brand from the Sprott Center for Stem Cell Research in Ottawa, Canada. They found the following:
    •    Components of the UTX demethylase complex interact with and co-activate TAL1.
    •    Over 80% of TAL1-bound sites are co-occupied by UTX. These sites are depleted of the repressive H3K27me3 mark.
    •    TAL1/UTX-co-bound genes that are downregulated upon TAL1 knockdown, are also downregulated upon UTX knockdown.
    •    UTX knockdown inTAL1-positive T-ALL cells leads to an increase in apoptosis and decrease in cell growth.
    •    TAL1-positive T-ALL cell growth is dependent on the demethylase activity of UTX.
    •    Pharmacological inhibition of UTX with GSK-J4 results in the selective elimination of TAL-1 positive cells.
    Overall, these results show that UTX is a coactivator of the TAL1 transcriptional regulatory program in T-ALL through removal of the H3K27me3 repressive mark. Inhibition by GSK-J4 is a promising epigenetic therapy for TAL1-positive T-AL
    T cell acute lymphoblastic leukemias (T-ALLs) are aggressive hematological tumors that vary in their genetic abnormalities and prognoses. In particular, TAL-1 positive T-ALLs have a poor prognosis compared with other types. 

    TAL-1 has been shown to control expression of genes necessary for cell growth and maintenance. A team led by Marjorie Brand from the Sprott Center for Stem Cell Research in Ottawa, Canada sought to understand the molecular mechanism though which TAL-1 regulates transcription of its target genes. They found the following:

    • Components of the UTX demethylase complex interact with and co-activate TAL-1.
    • Over 80% of TAL1-bound sites are co-occupied by UTX. These sites are depleted of the repressive H3K27me3 mark.
    • TAL1/UTX-co-bound genes that are downregulated upon TAL1 knockdown, are also downregulated upon UTX knockdown.
    • UTX knockdown in TAL-1-positive T-ALL cells leads to an increase in apoptosis and decrease in cell growth.
    • TAL1-positive T-ALL cell growth is dependent on the demethylase activity of UTX.
    • Pharmacological inhibition of UTX with GSK-J4 results in the selective elimination of TAL-1 positive cells.
    Overall, these results show that UTX coactivates the TAL-1 transcriptional regulatory program in T-ALL through removal of the H3K27me3 repressive mark. Inhibition by GSK-J4 is a promising epigenetic therapy for TAL1-positive T-ALL.

    Read the full paper in Genes and Development, March 2016.


    Sperm is epigenetically programmed to regulate gene transcription in embryos

    The role of sperm in embryonic gene expression

    The epigenetic state of the sperm nucleus has been suggested to influence transcription in the embryo. However, this hypothesis has recently been questioned.

    By comparing the development of sperm and spermatid-derived frog embryos, a team led by Jerome Jullien from the University of Cambridge, UK investigated the role of sperm in embryonic development. They found the following:

    • Sperm-derived embryos develop significantly better than spermatid-derived embryos.
    • In spermatid-derived embryos, several development-related genes are upregulated.
    • Repressive H3K27me3 marks are over-represented in sperm at genes that are differentially expressed in haploid embryos, whereas in spermatids, H3K27me3 co-exists with activating H3K4me2/3 on these genes.
    • Removal of H3K4me2/3 from H3K27 marked genes during the spermatid to sperm maturation is necessary for their proper expression in embryos.

    The results in the paper show that correct gene programming of paternal chromatin relies on effective H3K27me3-mediated repression at the spermatid to sperm transition.

    Read the full paper in Genome Research, March 2016.

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