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The reference human genome sequence set the stage for studies of genetic variation and its association with human disease, but epigenomic studies lack a similar reference. To address this need, the NIH Roadmap Epigenomics Consortium generated the largest collection so far of human epigenomes for primary cells and tissues. Here we describe the integrative analysis of 111 reference human epigenomes generated as part of the programme, profiled for histone modification patterns, DNA accessibility, DNA methylation and RNA expression. We establish global maps of regulatory elements, define regulatory modules of coordinated activity, and their likely activators and repressors. We show that disease- and trait-associated genetic variants are enriched in tissue-specific epigenomic marks, revealing biologically relevant cell types for diverse human traits, and providing a resource for interpreting the molecular basis of human disease. Our results demonstrate the central role of epigenomic information for understanding gene regulation, cellular differentiation and human disease.

Integrative analysis of 111 reference human epigenomes

Rapid improvements in sequencing and array-based platforms are resulting in a flood of diverse genome-wide data, including data from exome and whole-genome sequencing, epigenetic surveys, expression profiling of coding and noncoding RNAs, single nucleotide polymorphism (SNP) and copy number profiling, and functional assays. Analysis of these large, diverse data sets holds the promise of a more comprehensive understanding of the genome and its relation to human disease. Experienced and knowledgeable human review is an essential component of this process, complementing computational approaches. This calls for efficient and intuitive visualization tools able to scale to very large data sets and to flexibly integrate multiple data types, including clinical data. However, the sheer volume and scope of data pose a significant challenge to the development of such tools.

Integrative Genomics Viewer

Cell fate is controlled by complex networks that link chromatin features like DNA methylation, histone modifications, nucleosome positioning and transcription factor (TF) binding. A particular inte...

8 Interplay of nucleosome repositioning, DNA methylation and transcription factor binding during stem cell development

The concept of Science 2.0 was introduced almost a decade ago to describe the new generation of online-based tools for researchers allowing easier data sharing, collaboration and publishing. Although technically sound, the concept still does not work as expected. Here we provide a systematic line of arguments to modify the concept of Science 2.0, making it more consistent with the spirit and traditions of science and Internet. Our first correction to the Science 2.0 paradigm concerns the open-access publication models charging fees to the authors. As discussed elsewhere, we show that the monopoly of such publishing models increases biases and inequalities in the representation of scientific ideas based on the author's income. Our second correction concerns post-publication comments online, which are all essentially non-anonymous in the current Science 2.0 paradigm. We conclude that scientific post-publication discussions require special anonymization systems. We further analyze the reasons of the failure of the current post-publication peer-review models and suggest what needs to be changed in Science 3.0 to convert Internet into a large journal club.

Science 3.0: Corrections to the Science 2.0 paradigm

Mesenchymal stem cells (MSCs) are part of the tumour microenvironment and have been implicated in tumour progression. We found the number of MSCs significantly increased in tumour-burdened mice driven by Fas-threshold signalling. Consequently, MSCs lacking Fas lost their ability to induce metastasis development in a pancreatic cancer model. Mixing of MSCs with pancreatic cancer cells led to sustained production of the pro-metastatic cytokines CCL2 and IL6 by the stem cells. The levels of these cytokines depended on the number of MSCs, linking Fas-mediated MSC-proliferation to their capacity to promote tumour progression. Furthermore, we discovered that CCL2 and IL6 were induced by pancreatic cancer cell-derived IL1. Analysis of patient transcriptomic data revealed that high FasL expression correlates with high levels of MSC markers as well as increased IL6 and CCL2 in pancreatic tumours. Moreover, both FasL and CCL2 are linked to elevated levels of markers specific for monocytes known to possess further pro-metastatic activities. These results confirm our experimental findings of a FasL-MSC-IL1-CCL2/IL6 axis in pancreatic cancer and highlight the role MSCs play in tumour progression.

/pdf/fas-threshold-signalling-in-mscs-causes-tumour-progression-5bwbvqmv5h.pdf

Fas-threshold signalling in MSCs causes tumour progression and metastasis

One of the least understood properties of chromatin is the ability of its similar regions to recognise each other through weak interactions. Theories based on electrostatic interactions between helical macromolecules suggest that the ability to recognize sequence homology is an innate property of the non-ideal helical structure of DNA. However, this theory does not account for nucleosomal packing of DNA. Can homologous DNA sequences recognize each other while wrapped up in the nucleosomes? Can structural homology arise at the level of nucleosome arrays? Here we present a theoretical investigation of the recognition-potential-well between chromatin fibers sliding against each other. This well is different to the one predicted and observed for bare DNA; the minima in energy do not correspond to literal juxtaposition, but are shifted by approximately half the nucleosome repeat length. The presence of this potential-well suggests that nucleosome positioning may induce mutual sequence recognition between chromatin fibers and facilitate formation of chromatin nanodomains. This has implications for nucleosome arrays enclosed between CTCF-cohesin boundaries, which may form stiffer stem-like structures instead of flexible entropically favourable loops. We also consider switches between chromatin states, e.g., through acetylation/deacetylation of histones, and discuss nucleosome-induced recognition as a precursory stage of genetic recombination.

/pdf/nucleosome-induced-homology-recognition-in-chromatin-3adv55guja.pdf

Nucleosome induced homology recognition in chromatin

CTCF is an evolutionarily conserved and ubiquitously expressed architectural protein regulating a plethora of cellular functions via different molecular mechanisms. CTCF can undergo a number of post-translational modifications which change its properties and functions. One such modifications linked to cancer is poly(ADP-ribosyl)ation (PARylation). The highly PARylated CTCF form has an apparent molecular mass of 180 kDa (referred to as CTCF180), which can be distinguished from hypo- and non-PARylated CTCF with the apparent molecular mass of 130 kDa (referred to as CTCF130). The existing data accumulated so far have been mainly related to CTCF130. However, the properties of CTCF180 are not well understood despite its abundance in a number of primary tissues. In this study we performed ChIP-seq and RNA-seq analyses in human breast cells 226LDM, which display predominantly CTCF130 when proliferating, but CTCF180 upon cell cycle arrest. We observed that in the arrested cells the majority of sites lost CTCF, whereas fewer sites gained CTCF or remain bound (i.e. common sites). The classical CTCF binding motif was found in the lost and common, but not in the gained sites. The changes in CTCF occupancies in the lost and common sites were associated with increased chromatin densities and altered expression from the neighboring genes. Based on these results we propose a model integrating the CTCF130/180 transition with CTCF-DNA binding and gene expression changes. This study also issues an important cautionary note concerning the design and interpretation of any experiments using cells and tissues where CTCF180 may be present.

https://www.biorxiv.org/content/biorxiv/early/2017/08/11/175448.full.pdf

Vladimir B. Teif

Papers

8 Interplay of nucleosome repositioning, DNA methylation and transcription factor binding during stem cell development

Science 3.0: Corrections to the Science 2.0 paradigm

Fas-threshold signalling in MSCs causes tumour progression and metastasis

Nucleosome induced homology recognition in chromatin

Poly(ADP-ribosyl)ation associated changes in CTCF-chromatin binding and gene expression in breast cells