アブカムでは最適な動作のために Google Chrome など最新ブラウザでの閲覧を推奨します。
TET2 loss leads to leukemogenesis by DNA hypermethlation
The TET family of proteins play an essential role in DNA demethylation by converting 5-methylcytosine (5-mC) to 5-hydroxymethylcytosine (5-hmC). TET2 is frequently mutated in hematological cancers including acute myeloid leukemia (AML).
A team led by Kristian Helin from Biotech Research and Innovation Centre, University of Copenhagen and The Danish Stem Cell Centre sought to understand the role of TET2 mutations in DNA methylation and development of leukemia. Using a mouse model for TET2-deficient AML found that:
The authors demonstrate that loss of TET2 leads to genome-wide increase in DNA methylation of active enhancers, and propose that combined silencing of tumor suppressor genese contributes to tumorigenesis in AML.
Read the full paper in Genes and Development, April 2015.
Interested in DNA methylation? Take a look at all our DNA methylation resources.
New technique for the discovery of lncRNA binding proteins
RNA binding proteins play an important part in long non-coding RNA (lncRNA)-mediated gene regulation, and identification of such proteins is critical for understanding the functioning of lncRNAs. Although tools have been developed to identify lncRNAs that bind to specific proteins, there is no ideal strategy to identify the proteins that bind to specific lncRNAs.
A team led by Howard Chang from Stanford University School of Medicine has developed comprehensive identification of RNA binding proteins by mass spectrometry (ChIRP-MS) to identify endogenous protein partners associated with specific RNAs.
Using this technique, the team investigated proteins that bind to Xist, a lncRNA essential for X inactivation. They found that:
These data show that the Xist lncRNA binds with numerous proteins to coordinate chromatin spreading and silencing. This work paves the way for future structure-function analysis of Xist and its interacting proteins.
Read the full paper in Cell, April 2015.
YAP and TAZ act as transcriptional repressors as well as promoters
YAP and TAZ are transcriptional co-activators that are opposed by the Hippo tumor-suppressor pathway and overexpression of these factors leads to cancer development. Numerous genes have been identified that are upregulated by YAP/TAZ; however, these fail to completely account for the YAP/TAZ overexpression phenotype.
To further understand how YAP/TAZ functions in oncogenesis, Minchul Kim, Dai-Sik Lim and colleagues from the Korea Advanced Institute of Science and Technology and M.D. Anderson Cancer Center in Texas investigated whether YAP/TAZ could act as transcriptional co-repressors of antiproliferative and cell-death inducing genes.
They found that:
The data presented in this paper demonstrate that YAP/TAZ can act as transcriptional co-repressors. this suggests that they can function as oncogenes by repressing antiproliferative and cell-death inducing genes. and opens a new avenue for understanding the Hippo signaling pathway.
Read the full paper in Cell Reports, April 2015.
Mechanistic basis of target recognition by pioneer transcription factors
Pioneer transcription factors, including FoxA, have the ability to access silent chromatin to initiate cell fate changes. Although it is known that FoxA binds directly to DNA using a DNA binding domain that resembles linker histones, whether other pioneer transcription factors contain structures allowing direct binding to nucleosomes has not been assessed.
A team led by Kenneth Zaret at the University of Pennsylvania has investigated the nucleosome and chromatin targeting activities of the transcription factors that reprogram somatic cells to pluripotency; Oct4, Sox2, Klf4 and c-Myc.
They found that:
This paper has demonstrated how pioneer factors are able to target sites within silent chromatin. Understanding the mechanistic basis behind target recognition by transcription factors paves the way to being able to control the process of transcription factor binding and cell fate determination.
Read the full paper in Cell, April 2015.
H3K9 methylation marks are actively removed to prevent inheritance
Histone H3 lysine 9 methylation (H3K9me) is involved in the formation of constitutive heterochromatin. However, the heritability of H3K9me has not previously been demonstrated.
Fission yeast does not have DNA methylation, and has a single methylatransferase (Clr4) responsible for H3K9me-dependant heterochromatin, making analysis of heritability more straightforward than in eukaryotic systems.
Pauline Audergon, Robin Allshire and colleagues from the University of Edinburgh used fission yeast as a model to investigate epigenetic heritablility of H3K9me. By constitutively tethering Clr4 to euchromatin, an extensive domain of H3K9me-dependent heterochromatin is assembled. Using this system, the authors found that:
The data presented in this paper demonstrate that H3K9 methylation is a heritable epigenetic mark whose transmission is usually countered by its active removal, preventing the unauthorized inheritance of heterochromatin. This represents a built-in safety mechanism to avoid potentially deleterious gene silencing.
Read the full paper in Science, April 2015.
FBXL10 deficiency leads to aberrant DNA methylation
FBXL10 is a multidomain chromosomal protein that binds to CpG-dense promoters, and is bound at the majority of promoter-associated CpG islands in the mouse genome. Mutations affecting FBXL10 are commonly found in diseases including human diffuse large B cell lymphoma and transposon-induced mouse lymphoma.
Mathieu Boulard and colleagues from the College of Physicians and Surgeons of Columbia University and Washington University School of Medicine investigated the biological function of FBXL10. Using FBXL10-mutant mouse embryos, they found that:
The data presented in this paper indicate that Polycomb domains recruit DNA methyltransferase, and that FBXL10 prevents de novo methylation at PRC1 and PRC2 bound DNA sequences. This exciting development is the first example of a protein necessary for protection of DNA from hypermethlation.
Read the full paper in Nature Genetics, April 2015.
Find out more about the role of Polycombs in cancer.
A poised epigenetic state at enhancers confers developmental competence
Developmental competence refers to the ability of progenitor cells to appropriately interpret and respond to inductive cues from their environment. The mechanisms that render cells developmentally competent is currently unknown.
To investigate whether enhancer epigenetic state determines developmental competence, Allen Wang and colleagues from the University of California, San Diego, the University of Pennsylvania and Pennsylvania State University developed maps of enhancer-related chromatin modifications throughout human embryonic stem cell differentiation.
By looking at endodermal and pancreatic development, the team found that:
The data presented in this paper suggest that developmental competence is conferred by the establishment of a poised chromatin state at enhancers that allows recognition and binding by pioneer transcription factors.
Find the full paper in Cell Stem Cell, April 2015.