Epigenetics: traces of trauma and acquired characteristics are detectable over generations

Traumatic experiences leave traces in the activity of genes, cause changes in behaviour and mental disorders and are also passed on to future generations. But a positive and stimulating environment for the offspring can eliminate these traces. This is shown by studies on mice by Professor Isabelle Mansuy of the University and ETH Zurich, Switzerland. As Professor Mansuy will report (10 July) at the FENS Forum of Neuroscience in Berlin, these epigenetic changes, which do not alter the code of the genes themselves but their activity, are detectable not only in the nerve cells of the brain, but also in blood and germ cells – which might have an effect on the function of organs. (Mehr in: Pressemitteilungen – idw – Informationsdienst Wissenschaft)

Probing RNA epigenetics and chromatin structures to predict drug resistance in leukemia

A research team has begun to unravel the role of RNA epigenetics and chromatin structure in the regulation of 5-azacytidine, a DNA hypomethylating agent in certain leukemias. The results could lead to novel strategies and biomarkers that could reduce the risk of drug resistance. (Mehr in: Cancer News — ScienceDaily)

Blocking action of gene enhancers halts spread of tumor cells

In one of the first successes of its kind, researchers have inhibited the spreading of cancer cells from one part of the body to another. In doing so, they relied on a new model of how cancer metastasizes that emphasizes epigenetics, which examines how genes are turned on and off. (Mehr in: Cancer News — ScienceDaily)

After the epigenome: The epitranscriptome

A new article explains that RNA also has its own spelling and grammar, just like DNA. These ‚epigenetics of RNA‘ are called epitranscriptome. (Mehr in: Cancer News — ScienceDaily)

Epigenetics provides new insights into the pathogenesis of lymphoma

Cancer cells have a different DNA methylation pattern from that of healthy cells. These patterns can be used to explain tumor-specific deviations in gene expression and to identify biomarkers for the detection of tumors, as well as associated prognosis and treatment planning. This is all possible thanks to epigenetics. Epigenetics looks at special regulation mechanisms, such as DNA methylation and histone modifications, which determine the gene expression pattern of different types of cell and are passed on to daughter cells, without there being any specific changes to the DNA base sequence. Using this technology, it is now also possible to identify the original tumor cells, by comparing them with healthy cells. (Mehr in: Cancer News — ScienceDaily)

The impact of epigenetics on brain development

Scientists of CNMPB, MPIbpc and DZNE in Göttingen describe a molecular mechanism that controls global epigenetic programs in brain development. Published in Cell Reports. (Mehr in: Pressemitteilungen – idw – Informationsdienst Wissenschaft)

Linking gene expression, DNA methylation in single cells

A new single-cell genomics protocol allows researchers to study links between DNA modifications (methylation) and the activity of a gene. The method is the first to enable parallel profiling of the transcriptome and epigenome of a single cell. The researchers used the method to reveal new epigenome-transcriptome associations relevant to the regulation of pluripotency in mouse embryonic stem cells; The method is potentially transformative for epigenetics research, as it reveals unprecedented detail of the epigenetic control of genes. (Mehr in: Cancer News — ScienceDaily)

Like father like son: Epigenetics in wild guinea pigs

Fathers are able to adjust to increasing temperatures within their own lifetime and do transmit this information to their offspring. This has now been shown for the first time in a wild animal. The findings were the result of a project within the Joint Initiative for Research and Innovation and have been published in the scientific journal “Molecular Ecology”. (Mehr in: Pressemitteilungen – idw – Informationsdienst Wissenschaft)

Epigenetic discovery suggests DNA modifications more diverse than previously thought

The world of epigenetics — where molecular ’switches‘ attached to DNA turn genes on and off — has just got bigger with a new discovery that suggests that many more DNA modifications than previously thought may exist in human, mouse and other vertebrates. (Mehr in: Cancer News — ScienceDaily)

Differences between tumors of younger and older colorectal cancer patients

Tumors in younger colorectal cancer patients may be molecularly distinct from those of older patients, and that these differences are related to the way genes are switched on and off (epigenetics) in the tumors of the younger patients and may lead to better treatment options. (Mehr in: Cancer News — ScienceDaily)

A global assessment of cancer genomic alterations in epigenetic mechanisms

Muhammad A Shah, Emily L Denton, Cheryl H Arrowsmith, Mathieu Lupien and Matthieu Schapira

Abstract

Background

The notion that epigenetic mechanisms may be central to cancer initiation and progression is supported by recent next-generation sequencing efforts revealing that genes involved in chromatin-mediated signaling are recurrently mutated in cancer patients.

Results

Here, we analyze mutational and transcriptional profiles from TCGA and the ICGC across a collection 441 chromatin factors and histones. Chromatin factors essential for rapid replication are frequently overexpressed, and those that maintain genome stability frequently mutated. We identify novel mutation hotspots such as K36M in histone H3.1, and uncover a general trend in which transcriptional profiles and somatic mutations in tumor samples favor increased transcriptionally repressive histone methylation, and defective chromatin remodeling.

Conclusions

This unbiased approach confirms previously published data, uncovers novel cancer-associated aberrations targeting epigenetic mechanisms, and justifies continued monitoring of chromatin-related alterations as a class, as more cancer types and distinct cancer stages are represented in cancer genomics data repositories.

Continue reading „A global assessment of cancer genomic alterations in epigenetic mechanisms“

Three-dimensional super-resolution microscopy of the inactive X chromosome territory reveals a collapse of its active nuclear compartment harboring distinct Xist RNA foci

3D-SIM-based DAPI intensity classification in the Barr body versus the entire nucleus of C2C12 cells. (A) Mid z-section of a DAPI-stained nucleus. The area below the dashed line illustrates the resolution level obtained by wide-field deconvolution microscopy, for comparison. Inset magnifications show the non-uniformly compacted structure of the Barr body resolvable with 3D-SIM (1) and an arbitrary autosomal region with CDCs (2). Scale bars: 5 μm, insets 1 μm. (B) X chromosome-specific painting (green) of Xi (left) and Xa territories (right) of the same nucleus in different z-sections. Note the high convergence between the painted Xi and the DAPI visualized Barr body (arrowheads). Scale bars: 2 μm, insets 1 μm. (C) 3D DAPI intensity classification exemplified for the nucleus shown in (A). Seven DAPI intensity classes displayed in false-color code ranging from class 1 (blue) representing pixels close to background intensity, largely representing the IC, up to class 7 (white) representing pixels with highest density, mainly associated with chromocenters. Framed areas of the Barr body (inset 1) and a representative autosomal region (inset 2) are shown on the right at resolution levels of 3D-SIM, deconvolution and conventional wide-field microscopy. The Xi territory pervaded by lower DAPI intensities becomes evident only at 3D-SIM resolution, whereas both wide-field and deconvolution microscopy imply a concentric increase of density in the Barr body. In the autosomal region, chromatin assigned to classes 2 to 3 lines compacted CDCs, represented by classes 4 to 6. (D) Left: average DAPI intensity classification profiles with standard deviations evaluated for entire nuclear volumes or the Barr body region only (dark grey bars). Right: over/underrepresentation of the average DAPI intensity class fraction sizes in the Barr body versus entire nuclear volumes (n = 12). Distribution differences on classes between Xi and entire nucleus P <0.001. 3D-SIM, three-dimensional structured illumination microscopy; CDC, chromatin domain cluster; DAPI, 4',6-diamidino-2-phenylindole; FISH, fluorescence in situ hybridization; IC, interchromatin compartment; Xa, active X chromosome; Xi, inactive X chromosome. Smeets et al. Epigenetics & Chromatin 2014 7:8   doi:10.1186/1756-8935-7-8
3D-SIM-based DAPI intensity classification in the Barr body versus the entire nucleus of C2C12 cells. (A) Mid z-section of a DAPI-stained nucleus. The area below the dashed line illustrates the resolution level obtained by wide-field deconvolution microscopy, for comparison. Inset magnifications show the non-uniformly compacted structure of the Barr body resolvable with 3D-SIM (1) and an arbitrary autosomal region with CDCs (2). Scale bars: 5 μm, insets 1 μm. (B) X chromosome-specific painting (green) of Xi (left) and Xa territories (right) of the same nucleus in different z-sections. Note the high convergence between the painted Xi and the DAPI visualized Barr body (arrowheads). Scale bars: 2 μm, insets 1 μm. (C) 3D DAPI intensity classification exemplified for the nucleus shown in (A). Seven DAPI intensity classes displayed in false-color code ranging from class 1 (blue) representing pixels close to background intensity, largely representing the IC, up to class 7 (white) representing pixels with highest density, mainly associated with chromocenters. Framed areas of the Barr body (inset 1) and a representative autosomal region (inset 2) are shown on the right at resolution levels of 3D-SIM, deconvolution and conventional wide-field microscopy. The Xi territory pervaded by lower DAPI intensities becomes evident only at 3D-SIM resolution, whereas both wide-field and deconvolution microscopy imply a concentric increase of density in the Barr body. In the autosomal region, chromatin assigned to classes 2 to 3 lines compacted CDCs, represented by classes 4 to 6. (D) Left: average DAPI intensity classification profiles with standard deviations evaluated for entire nuclear volumes or the Barr body region only (dark grey bars). Right: over/underrepresentation of the average DAPI intensity class fraction sizes in the Barr body versus entire nuclear volumes (n = 12). Distribution differences on classes between Xi and entire nucleus P Smeets et al. Epigenetics & Chromatin 2014 7:8 doi:10.1186/1756-8935-7-8

Daniel Smeets, Yolanda Markaki, Volker J Schmid, Felix Kraus, Anna Tattermusch, Andrea Cerase, Michael Sterr, Susanne Fiedler, Justin Demmerle, Jens Popken, Heinrich Leonhardt, Neil Brockdorff, Thomas Cremer1, Lothar Schermelleh and Marion Cremer

Abstract

Background

A Xist RNA decorated Barr body is the structural hallmark of the compacted inactive X territory in female mammals. Using super-resolution three-dimensional structured illumination microscopy (3D-SIM) and quantitative image analysis, we compared its ultrastructure with active chromosome territories (CTs) in human and mouse somatic cells, and explored the spatio-temporal process of Barr body formation at onset of inactivation in early differentiating mouse embryonic stem cells (ESCs).

Results

We demonstrate that all CTs are composed of structurally linked chromatin domain clusters (CDCs). In active CTs the periphery of CDCs harbors low-density chromatin enriched with transcriptionally competent markers, called the perichromatin region (PR). The PR borders on a contiguous channel system, the interchromatin compartment (IC), which starts at nuclear pores and pervades CTs. We propose that the PR and macromolecular complexes in IC channels together form the transcriptionally permissive active nuclear compartment (ANC). The Barr body differs from active CTs by a partially collapsed ANC with CDCs coming significantly closer together, although a rudimentary IC channel system connected to nuclear pores is maintained. Distinct Xist RNA foci, closely adjacent to the nuclear matrix scaffold attachment factor-A (SAF-A) localize throughout Xi along the rudimentary ANC. In early differentiating ESCs initial Xist RNA spreading precedes Barr body formation, which occurs concurrent with the subsequent exclusion of RNA polymerase II (RNAP II). Induction of a transgenic autosomal Xist RNA in a male ESC triggers the formation of an ‘autosomal Barr body’ with less compacted chromatin and incomplete RNAP II exclusion.

Conclusions

3D-SIM provides experimental evidence for profound differences between the functional architecture of transcriptionally active CTs and the Barr body. Basic structural features of CT organization such as CDCs and IC channels are however still recognized, arguing against a uniform compaction of the Barr body at the nucleosome level. The localization of distinct Xist RNA foci at boundaries of the rudimentary ANC may be considered as snap-shots of a dynamic interaction with silenced genes. Enrichment of SAF-A within Xi territories and its close spatial association with Xist RNA suggests their cooperative function for structural organization of Xi.

Continue reading „Three-dimensional super-resolution microscopy of the inactive X chromosome territory reveals a collapse of its active nuclear compartment harboring distinct Xist RNA foci“