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Histone phosphorylation enables differential H3 inheritance by daughter cells
To ensure that stem cell populations are maintained, adult stem cells undergo asymmetric cell division to generate a self-renewed stem cell and a differentiated daughter cell. Epigenetics is known to play an important role in ensuring proper maintenance and differentiation of stem cell populations, but the molecular pathways behind this are not fully understood.
Previous research showed that during asymmetric division of Drosophila male germline stem cells (GSCs), pre-existing histone H3 is selectively incorporated into the self-renewed GSC daughter cell. In this paper, a team led by Xin Chen from John Hopkins University in Baltimore propose and test the hypothesis that asymmetric histone inheritance allows GSCs to establish unique epigenetic identities in each of the two daughter cells. Here is what they found:
The authors have demonstrated that H3T3P is differentially deposited on existing and newly-synthesized H3, and that this coordinates asymmetric H3 segregation into daughter cells.
Read the full paper in Cell, November 2015.
The Ikaros transcription factor regulates PRC2 function to repress gene expression in T cells
T lymphocytes develop from hematopoetic stem cells (HSCs) in a process that requires the loss of stem cell properties and the activation of T lymphocyte-specific programmes. Epigenetic factors are important mediators of this switch, but the effect of specific regulators in this process has not been established.
To find out more about epigenetics in T cell development, a team led by Philippe Kastner from the University of Strasbourg in France looked at the role of Ikaros; a transcription factor that is essential for T cell development.
These results indicate that by mediating PRC2 function, Ikaros is a key repressor of gene expression in developing T cells.
Read the full paper in Nature Communications, November 2015.
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Metabolic characterization of the naive-to-primed stem cell transition
Embryonic stem cells (ESCs) have two states of pluripotency; naive preimplantation stem cells have high developmental potential and post-implantation primed ESCs have more limited potential. During the transition between naive and primed states, ESCs undergo a distinct change in both metabolic and epigenetic profiles.
To explore this transition further, a team led by Hannele Ruohola-Baker from the University of Washington investigated regulation and metabolomics as cells progress from a naive to primed state.
This study demonstrates that histone marks are regulated by SAM levels and NNMT in nave hESCs. The authors propose that SAM activates PRC2, increasing repressive H3K27me3 epigenetic marks on the promoters of genes that regulate the naive to primed transition.
Read the full paper in Nature Cell Biology, November 2015.
EZH2 stabilization of PRC2 is crucial for SWI/SNF-mutant cancers
SWI/SNF complexes are important chromatin remodelers that, when mutated, can lead to cancer development. However, it is unknown if other factors contribute to the growth of SWI/SNF-mutant cancers.
A team led by Charles Roberts from the Dana-Farber Cancer Institute in Boston, Massachusetts investigated whether SWI/SNF mutant cancers are dependent on EZH2; a Polycomb repressive complex 2 (PRC2) component with antagonistic effects to SWI/SNF. Here is what they found:
Collectively, these results show that the dependence on EZH2 in some SWI/SNF-mutant cancer is largely dictated by a non-enzymatic contribution of EZH2, potentially by stabilizating the PRC2 complex. It also highlights that inhibitors of EZH2 enzymatic may not fully suppress its oncogenic activity.
Read the full paper in Nature Medicine, November 2015.
Bivalent domains maintain developmental genes in a poised state
Lineage committed multipotent progenitor cells are essential for self-renewal and repair in adult tissues. These cells are maintained in an undifferentiated state, but poised for differentation into cells of a specific lineage; however, the mechanisms that maintain cells in this state is currently unclear.
To understand this further, a team led by Juro Sakai from the University of Tokyo looked at bivalent chromatin domains that contain both activating and inactivating epigenetic marks in mesenchymal stem cells and preadipocytes. They uncovered the following:
This paper highlights the role of H3K4/H3K9me3 bivalent domains in maintaining developmental genes in a poised state and restricting the differentiation potential of preadipocytes.
Read the full paper in Molecular Cell, November 2015.
Displacement of water molecules is essential for trimethyllysine-reader recognition
Histone lysine methylation has a huge impact on global gene activation and repression. Interaction between histone methylation and effectors – proteins that recognize modified lysine and effect downstream processes – occurs through an interaction between the positively charged side chain of trimethyllysine (Kme3) and the elecron-rich aromatic cage present in effector proteins.
A team led by Jasmin Mecinović from Radboud University in the Netherlands used a computational approach to further characterize this interaction. They found the following:
These data indicate that as well as cation-π interactions, favorable release of water molecules from the aromatic cages of reader proteins is required for specific interation between trimethyllysine histones and their effector proteins. This is the first study to highlight the importance of water molecules in this interaction.
Read the full paper in Nature Communications, November 2015.
A new technique to map in vivo miRNA targets
MicroRNAs (miRNAs) post-transcriptionally silence genes by directing Argonaute to messenger RNA. miRNAs recognize target mRNA sequences through complementary base pairing; however, most in vivo miRNA targets are unknown.
Identification of miRNA targets is challenging, but a team led by Robert Darnell from the Rockefeller University in New York has developed a new technique that ligates miRNAs to their endogenous mRNAs. By using this technique – called covalent ligation of endogenous Argonaute-bound RNAs with crosslink immunoprecipitatiom (CLEAR-CLIP) – the team mapped 130,000 miRNA-target interactions in the mouse brain and 35,000 in human hepatoma cells.
This technique enables identification of in vivo miRNA sites. The authors have used it to demonstrate that most interactions combine seed-based pairing with distinct miRNA-specific patterns of auxiliary pairing.
Read the full in Nature Communications, November 2015.