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Here the authors show that differentiation of haematopoietic stem cells into mature blood cells is primed by cell type-specific transcription factors at the enhancer level during early differentiation, before they confere promoter-driven growth arrest, and activate post-mitotic terminal differentiation.

Hedehus et al. show that H3K9me3 and H3K36me3 can only partially compensate for loss of H3K27me3, supporting the concept of a combinatorial histone code.

Specific patterns of post-translational modifications in chromatin structure are important factors in the regulation of gene expression, and when deregulated they can contribute to diseases including cancer and neurological disorders. Here, Helin and colleagues focus on the role of one class of chromatin-modifier enzymes — the histone lysine demethylases — highlighting their links to cancer and their potential to be therapeutically targeted.

In this Opinion article, the authors propose that the function of Polycomb repressive complex 2 (PRC2) in maintaining, rather than specifying, transcriptional repression can explain its seemingly contradictory roles in cancer.

With-No-lysine (K) kinase 1 (WNK1) is an atypical serine-threonine kinase that has been implicated in ion transport. Here, the authors show that WNK1 regulates amino acid transport and mTORC1 activity, and that the axis is a vulnerability for acute myeloid leukemia

Naïve pluripotency is characterized by distinctly open chromatin and repressed endogenous retroviruses. Here the authors show that MPP8 and its association with the core HUSH complex is essential for naïve pluripotent cells; also that repression of LINE1 elements by MPP8 does not require chromatin binding, nor H3K9me3.

The Polycomb group (PcG) proteins are transcriptional repressors that regulate lineage choices during development and differentiation and are often deregulated in cancer. How might they become deregulated and how does this contribute to tumorigenesis?

Histone demethylases are important for both chromatin structure and transcription. The insights being gained into their regulation and target specificity have important implications for both normal development and disease.

Although mechanisms wherein pre-existing H3K27 methylation directs recruitment of PRC2 to support its own maintenance have been proposed, H3K27 methylation patterns in mESCs are not dependent on self-autonomous epigenetic inheritance.

Although mutant H3K27M histones inhibit PRC2 in diffuse intrinsic pontine gliomas, these tumors exhibit significant amounts of PRC2 activity. The repression of several genes, including INK4A, by residual EZH2 activity is required for tumor growth, and EZH2 inhibitors therefore represent potential therapies for these patients.

Acute loss of H3K4me3 does not have detectable effects on transcriptional initiation, but leads to a widespread decrease in transcriptional output, an increase in RNA polymerase II pausing and slower elongation

Two human JmjC-domain-containing enzymes are shown to catalyse demethylation of histone H3K27me3, a histone modification mediated by polycomb proteins and associated with stem cell maintenance and differentiation

Hoffmann and colleagues report that the mammalian maternal-to-zygotic transition requires KDM4A-mediated removal of H3K9me3 from the broad H3K4me3 domains in oocytes.

Traditionally, maintenance of gene silencing by the Polycomb group proteins has been thought to involve recruitment of Polycomb repressive complex (PRC) 1 by PRC2-mediated trimethylation of K27 on histone H3. Three recent studies challenge this model by demonstrating that monoubiquitination of histone H2A, which is catalyzed by PRC1 complexes, can recruit PRC2 and potentiate its catalytic activity.

The chromatin mark H3K27me3 is transmitted during cell division by recruitment and binding of the PRC2 complex, which maintains the mark and leads to methylation of H3K27 on newly incorporated histones.

CRISPR editing of all 28 alleles encoding histones H3.1, H3.2 and H3.3 in mouse embryonic stem cells (mESCs) generates pan-H3K27R mutant mESCs, which are transcriptionally similar to PRC2-null mESCs. H3K27 acetylation is dispensable for gene derepression in mESCs and for gene activation in epiblast-like cells.

Limited perfusion of solid tumours produces a nutrient-deprived tumour core microenvironment. Low glutamine levels in the tumour core are now shown to lead to reduced levels of α-ketoglutarate and decreased histone demethylase activity, thereby promoting a less differentiated and more therapy-resistant state of the tumour cells.

Due to their role in regulating DNA-methylation patterns, the TET proteins, in particular TET2, have emerged as key participants in tumorigenesis. Now the spotlight shifts to TET1 and its role as a tumor suppressor in lymphomagenesis.

Oncogene-induced senescence (OIS) is a barrier to tumour progression. Here the authors identify the long non-coding RNA MIR31HG as a regulator of cellular senescence using the oncogene-induced senescence triggered by B-RAF expression in immortalized fibroblasts.

One of two papers in this issue that identifies enzymes capable of demethylating a tri-methyl group from Lys 9 of histone H3 — a mark required for the establishment of heterochromatin and previously considered to be stable. GASC1, a member of the JMJD2 enzyme family, can disrupt heterochromatin structure when overexpressed and may contribute to tumour development.

The arginine methyltransferase PRMT5 modifies the splicing regulator SRSF1 and affects acute myeloid leukemia cell survival by modulating SRSF1 function.

Specific chromatin features, especially histone H3 lysine 27 acetylation, are widely used to identify active enhancers, yet current methods are imprecise. New work suggests that histone H2B N terminus multisite lysine acetylation (H2BNTac) is a notable signature of active enhancers and could substantially improve enhancer prediction.

Polycomb proteins have a key role in regulating the expression of genes essential for development, differentiation and maintenance of cell fates. Here, Polycomb repressive complex 2 (PRC2) is shown to form a complex with JARID2, a Jumonji domain protein. JARID2 is required for the binding of Polycomb proteins to target genes in embryonic stem cells as well as for the proper differentiation of ES cells.

Successful immune-mediated tumor control in pancreatic cancer is severely hampered by its dense desmoplastic stroma. New work shows that EZH2 inhibition relieves the suppressive effect of tumor stroma on pro-inflammatory chemokine expression after therapy-induced senescence, boosting NK and T cell recruitment and immunological tumor control.

AKT inhibitors synergize with agents that suppress the histone methyltransferase EZH2 and promote robust tumour regression in multiple triple-negative breast cancer models in vivo by triggering an involution-like process.

Polycomb (PcG) proteins are known to promote cell proliferation by silencing expression of the tumour suppressor Ink4A-Arf. Piunti et al.show that PcG proteins also regulate tumour progression independently of this role, revealing a requirement for PRC1 and PRC2 in replication fork progression.

DNA hypomethylating agents (HMAs) are used for the treatment of myeloid malignancies, but their therapeutic effects are not satisfactory. Here, the authors show that inhibition of TOPORS, which encodes a ubiquitin E3 ligase, augments the efficacy of HMAs through DNMT1 stabilization.

TET2 mutations are frequent in myeloid malignancies and in elderly individuals with or without cytopenia. Here, the authors analyse the association between TET2 mutations and methylation changes in healthy elderly twins and patients with cytopenia and compare them to those from leukemia.

Self-renewal and differentiation of adult stem cells ensures tissue homeostasis. De Haan and colleagues find that the chromatin-associated polycomb protein Cbx7 ensures self-renewal of haematopoietic stem cells (HSCs), whereas other polycomb proteins, such as Cbx8, induce differentiation. They find that although genes targeted by Cbx8 are highly expressed in HSCs and repressed in progenitors, Cbx7 target genes have the opposite expression pattern.

The Polycomb repressive complexes PRC1 and PRC2 play a central role in developmental regulation of the genome in multicellular organisms. Here the authors describe how the PRC2 cofactor Jarid2 mediates the recruitment of the PRC2 complex to chromatin via interaction with H2AK119u1.

Little is known about the genetics of sclerosing stromal tumor of the ovary, a rare type of sex cord-stromal tumor. Here, the authors use sequencing strategies to show that in a cohort of 26 tumor samples 65% carry a FHL2-GLI2 fusion gene and demonstrate in vitro that the fusion gene has oncogenic properties.

Inhibition of the CDC25A phosphatase is critical for activation of the DNA damage-induced G2/M checkpoint. The DNA damage-activated kinase CHK1 phosphorylates the NIMA-related kinase NEK11, which in turn phosphorylates CDC25A to induce its degradation.

Here, the authors discuss the various roles of the HUSH transcriptional silencing complex and its dysregulation in disease.

Although IL-23 is expressed by psoriatic keratinocytes as well as immune cells, only the immune cell derived IL-23 is thought to be important for the development of psoriasis. Here the authors provide evidence that keratinocyte-produced IL-23 is sufficient to cause a chronic skin inflammation.

Shohreh Issazadeh-Navikas and colleagues report on a previously undescribed population of regulatory T (Treg) cells that accumulate in the CNS in response to autoimmune inflammation and are induced by interferon-β (IFN-β). These cells, termed FoxA1+ Treg cells, express the transcription factor FoxA1+, which is required for their development and function. Individuals with multiple sclerosis that respond to IFN-β have an increased frequency of FoxA1+ Treg cells, suggesting that the induction of these cells may account for some of the protective effects of IFN-β.

Polycomb group (PcG) proteins function within Polycomb repressive complexes (PRCs), which modify histones and other proteins and silence target genes. This Review highlights new insights into the role of PcG proteins in gene regulation, specifically in controlling self-renewal and differentiation of embryonic stem cells, and into how PRCs are targeted to chromatin.