ASH1-marked chromatin can be further modified by methylation of H3K27, and ASH1 catalytic activity modulates the accumulation of H3K27me2/3 both positively and negatively. These findings provide new insight into ASH1 function, H3K27me2/3 establishment, and repression in facultative heterochromatin. Linker histone H1 proteins bind to nucleosomes and facilitate chromatin compaction 1, although their biological functions are poorly understood.Mutations in the genes that encode H1 isoforms B-E (H1B, H1C, H1D and H1E; also known as H1-5, H1-2, H1-3 and H1-4, respectively) are highly recurrent in B cell lymphomas, but the pathogenic relevance of these mutations to cancer and the mechanisms. Installation To get started with your Chromation Spec Dev Kit you will need to install the USB driver and interface software for Windows. Download and install the USB driver. It is available directly from FTDI here.

• Drivers Chromatin Model
• Drivers Chromatin Definition
• Drivers Chromatin Vs

Monica Wang

• As part of the new class of Pew-Stewart Scholars, geneticist Chao Lu, PhD, is taking a close look at chromatin’s role in cancer and other human diseases.Work in the Lu lab has revealed that cancer-associated mutations in chromatin modulators are drivers of tumor development.
• Cancer is driven by somatic mutations in critical genes, but few non-coding drivers are known. In a pan-cancer analysis, Zhu et al. Identified frequently mutated, multi-tissue regulatory elements with chromatin loops to distal genes. Genomic deletion of one region caused deregulation of cancer genes, pathways, and proliferation in human cells.

Oncogenesis is often a slow process associated with the progressive accumulation of a complex network of genetic alterations, which, over time, dysregulate cellular proliferation and function. However, this aetiology is not the case for paediatric cancers—the discovery of recurrent histone mutations in children with cancer revealed that ‘oncohistones’ can have vast effects on gene expression and are the root causes of many aggressive paediatric cancers.

As essential components of chromatin, the core histones H2A, H2B, H3 and H4 not only create a structural backbone for eukaryotic DNA packaging, but are also crucial to the regulation of RNA replication, transcription and repair. The roles of histones in these cellular processes are regulated by their patterns of post-translational modifications, such as methylation or acetylation, and therefore depend on the activity of histone-modifying and chromatin-remodelling enzymes.

In 2012, two seminal studies revealed the presence of high-frequency somatic alterations in paediatric high-grade gliomas, including glioblastomas (GBMs). These mutations mainly affected the histone H3 genes H3-3A (encoding the histone variant H3.3) and H3C2 (encoding the canonical histone H3.1). Further studies confirmed that certain paediatric tumours often contain heterozygous missense mutations in H3 genes that do not cause early protein termination and loss, but instead result in gain-of-function changes that drive oncogenesis. These amino acid substitutions often occur in the highly conserved amino terminus of H3, specifically at amino acids K27, K36 and G34, which are associated with post-translational modification of H3. These findings suggest that oncohistones promote tumour initiation and progression by interfering with the regulation of transcription through changes in chromatin remodelling and accessibility.

In 2013, multiple studies reported that the H3 K27M oncohistone leads to a decrease in trimethylated H3K27 (H3K27me3)—a transcriptional repressor—by inhibiting the methyltransferase EZH2, the catalytic subunit of Polycomb enzyme repressive complex 2 (PRC2). Interestingly, residual PRC2 activity is required for tumour proliferation, and EZH2 inhibition has therefore been proposed as a therapeutic target. The loss of H3K27me3 has been associated with the upregulation of many genes involved in developmental neurogenesis.

In 2012, H3 G34R substitutions were also identified as recurrent GBM alterations. A subsequent study suggested that these oncohistones alter the interaction of H3K36me3 with its binding partners, thus leading to the upregulation of the MYCN oncogene, and G34R inhibition of KDM4 demethylases has also been reported. Moreover, H3 K36M alterations, which have been identified in chrondroblastomas and sarcomas, can inhibit several H3K36 methyltransferases. The consequent decrease in H3K36me was associated with an increase in H3K27me, which affected the activity of PRC1 complexes and led to the expression of genes known to block mesenchymal differentiation, thus potentially contributing to sarcoma development.

Notably, these different sets of oncohistone amino acid substitutions and the genes that they affect are specifically associated with distinct tumour types and anatomical locations. For example, whereas tumours with K27 alterations often occur in the pons and thalamus, G34 alterations are usually found in tumours that develop in the cerebral hemispheres. Moreover, despite the overall decrease in methylated K27 in tumours with K27M alterations, a 2017 report suggested that some loci (such as CDKN2A) retain H3K27me3, thereby leading to a selective gene-silencing programme that promotes oncogenesis while retaining the identity of the tumour cell of origin. Anatomical specificity might be explained by the differential gene expression patterns of canonical and variant H3 genes across different cell types. The expression of canonical histones is restricted to the DNA-replication phase of the cell cycle, whereas histone variants can be expressed throughout any phase of the cell cycle and progressively accumulate in long-lived cells. In addition, canonical H3.1 is dispersed through the genome, whereas the H3.3 variant is incorporated into distinct genomic regions, such as areas of active transcription or regulatory regions. Interestingly, a recent study of patient-derived glioma cell lines has suggested that H3 K27M-mediated loss of H3K27me3 might occur only when oncohistones are incorporated into the chromatin of dividing cells.

A 2019 report suggested that oncohistones might not be restricted to gliomas and sarcomas. Somatic alterations in all core histones have been identified in diverse tumour types. Whether these are driver or passenger mutations remains uncertain, but the locations of the affected residues indicate that, similarly to the first-identified GBM H3 oncohistones, these mutations may have the potential to substantially override normal patterns of gene expression by interfering with post-translational histone modifications and chromatin remodelling. Further downstream, these changes are associated with alterations in kinase signalling and cellular metabolism, although the underlying mechanisms remain unclear.

These advances in understanding the roles of oncohistones in cancer have revealed new therapeutic targets, and several histone deacetylase inhibitors and tyrosine kinase inhibitors are currently being tested in clinical trials. New precision medicine efforts, which assign therapeutic interventions in clinical trials according to genetic screening of tumours, should improve the chances of success.

Further reading

Behjati, S. et al. Distinct H3F3A and H3F3B driver mutations define chondroblastoma and giant cell tumor of bone. Nat. Genet. 45, 1479–1482 (2013).

Lewis, P. W. et al. Inhibition of PRC2 activity by a gain-of-function H3 mutation found in pediatric glioblastoma. Science 340, 857–861 (2013).

Bjerke, L. et al. Histone H3.3. mutations drive pediatric glioblastoma through upregulation of MYCN. Cancer Discov. 3, 512–519 (2013).

Bender, S. et al. Reduced H3K27me3 and DNA hypomethylation are major drivers of gene expression in K27M mutant pediatric high-grade gliomas. Cancer Cell24, 660–672 (2013).

Lu, C. et al. Histone H3K36 mutations promote sarcomagenesis through altered histone methylation landscape. Science352, 844–849 (2016).

Mohammad, F. et al. EZH2 is a potential therapeutic target for H3K27M-mutant pediatric gliomas. Nat. Med.23, 483–492 (2017).

Voon, H. S. P. Inhibition of a K9/K36 demethylase by an H3.3 point mutation found in paediatric glioblastoma. Nat. Commun. 9, 3142 (2018).

Larson, J. D. et al. Histone H3.3 K27M accelerates spontaneous brainstem glioma and drives restricted changes in bivalent gene expression. Cancer Cell35, 140–155 (2019).

Nacev, B. A. et al. The expanding landscape of ‘oncohistone’ mutations in human cancers. Nature567, 476-478 (2019).

Chung, C. et al. Integrated metabolic and epigenomic reprograming by H3K27M mutations in diffuse intrinsic pontine gliomas. Cancer Cell14, 334-349 (2020).

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Drivers Chromatin Model

A sugar rush can fuel many things. It can power the late-night experiments demanded by reviewer number 3 or it can drive tumor evolution. Fueled by both these factors, new insight into the linked metabolic-epigenetic mechanisms of metastasis comes at you from a collaborative effort led by the lab of Andrew Feinberg in the Center for Epigenetics at Johns Hopkins University School of Medicine.

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal cancer that is all too common. The mechanisms of its metastasis remain a mystery since both primary tumors and far-flung secondary (metastatic) tumors share the same driver mutations. By examining matched primary and metastatic PDAC lesions, the team was able study tumor evolution in extensively sequenced samples that had no metastasis-specific driver mutations. Thus, they had the perfect samples to study the epigenomic mechanisms of cancer’s spread, which they confirmed in cell lines.

Immunohistochemistry of histone post-translational modifications (PTMs) revealed global epigenomic reprogramming during the evolution of distant metastases. The team then characterized the specific locations of the modifications by launching an integrated assault on the epigenomic landscape. They used ChIP-seq to analyze histone PTMs (H3K9me2, H3K9me3, and H3K27me3 as marks of heterochromatin and H3K27ac and H3K36me3 as marks of euchromatin), whole-genome bisulfite sequencing (WGBS) for DNA methylation, and RNA-seq for gene expression.

Here’s what they found:

• The epigenomic reprogramming is targeted to thousands of large-scale euchromatin and heterochromatin domains.
  • The large heterochromatin domains are large organized chromatin (H3)K9-modications (LOCKs) domains and their partially overlapping large DNA-hypomethylated blocks.
  • They also came across a familiar and interesting hybrid feature, resembling LOCK euchromatin islands (LOCK-EIs). There are highly localized reciprocal changes to H3K27ac and H3K9me2, within promoters, coupled to similar reciprocal changes of H3K36me3 and H3K27me3, in gene bodies, within LOCK genes.
  • The team also found reprogramming in a unique subset of very large LOCK domains.
• A connection between metabolism and histone modifications, where distant metastases co-evolve a dependence on the oxidative branch of the pentose phosphate pathway (oxPPP).
  • This lets tumors binge on glucose to feed the metabolic sweet tooth that is critical to their growth in their new environment.
  • This mechanism was confirmed by inhibiting phosphogluconate dehydrogenase (PGD), a key enzyme in the oxPPP, either with RNAi or pharmacologically, which reversed the reprogrammed chromatin and gene expression, as well as the tumorigenesis.

Drivers Chromatin Definition

Overall, these findings detail a non-genetic form of natural selection critical to tumor evolution, where linked metabolic-epigenetic programs are selected for and allow distant metastases to take advantage of their new glucose rich environments.

Drivers Chromatin Vs

Offering a humble peek behind the scientific curtain, Feinberg concludes, “I would actually like to say something about peer review. We all complain about it but we are also the reviewers. In this case, the amount of work and resources doubled in response to reviewers’ criticisms, but in the end I thank them for that. The additional work made a much more convincing case that the epigenetic changes drive distant cancer metastasis and that they are linked to a metabolic pathway that we might be able to manipulate therapeutically, increasing the chances that this work will benefit patients’ lives.”

Catch all the evolutionary links over at Nature Genetics, January 2017