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Nina Koenecke, Jeff Johnston, Bjoern Gaertner, Malini Natarajan, Julia Zeitlinger
BACKGROUND: Drosophila dorso-ventral (DV) patterning is one of the best-understood regulatory networks to date, and illustrates the fundamental role of enhancers in controlling patterning, cell fate specification, and morphogenesis during development. Histone acetylation such as H3K27ac is an excellent marker for active enhancers, but it is challenging to obtain precise locations for enhancers as the highest levels of this modification flank the enhancer regions. How to best identify tissue-specific enhancers in a developmental system de novo with a minimal set of data is still unclear...
September 27, 2016: Genome Biology
Edwin Garcia, Annette Hayden, Charles Birts, Edward Britton, Andrew Cowie, Karen Pickard, Massimiliano Mellone, Clarisa Choh, Mathieu Derouet, Patrick Duriez, Fergus Noble, Michael J White, John N Primrose, Jonathan C Strefford, Matthew Rose-Zerilli, Gareth J Thomas, Yeng Ang, Andrew D Sharrocks, Rebecca C Fitzgerald, Timothy J Underwood
New biological tools are required to understand the functional significance of genetic events revealed by whole genome sequencing (WGS) studies in oesophageal adenocarcinoma (OAC). The MFD-1 cell line was isolated from a 55-year-old male with OAC without recombinant-DNA transformation. Somatic genetic variations from MFD-1, tumour, normal oesophagus, and leucocytes were analysed with SNP6. WGS was performed in tumour and leucocytes. RNAseq was performed in MFD-1, and two classic OAC cell lines FLO1 and OE33...
2016: Scientific Reports
Meital Gury-BenAri, Christoph A Thaiss, Nicolas Serafini, Deborah R Winter, Amir Giladi, David Lara-Astiaso, Maayan Levy, Tomer Meir Salame, Assaf Weiner, Eyal David, Hagit Shapiro, Mally Dori-Bachash, Meirav Pevsner-Fischer, Erika Lorenzo-Vivas, Hadas Keren-Shaul, Franziska Paul, Alon Harmelin, Gérard Eberl, Shalev Itzkovitz, Amos Tanay, James P Di Santo, Eran Elinav, Ido Amit
Innate lymphoid cells (ILCs) are critical modulators of mucosal immunity, inflammation, and tissue homeostasis, but their full spectrum of cellular states and regulatory landscapes remains elusive. Here, we combine genome-wide RNA-seq, ChIP-seq, and ATAC-seq to compare the transcriptional and epigenetic identity of small intestinal ILCs, identifying thousands of distinct gene profiles and regulatory elements. Single-cell RNA-seq and flow and mass cytometry analyses reveal compartmentalization of cytokine expression and metabolic activity within the three classical ILC subtypes and highlight transcriptional states beyond the current canonical classification...
August 25, 2016: Cell
A Fernández-Miñán, J Bessa, J J Tena, J L Gómez-Skarmeta
Accurate transcriptional control of genes is fundamental for the correct functioning of organs and developmental processes. This control depends on the interplay between the promoter of genes and other noncoding sequences, whose interaction is mediated by 3D chromatin arrangements. Thus, the detailed description of transcriptional regulatory landscapes is essential to understand the mechanisms of transcriptional regulation. However, to achieve that, two important challenges have to be faced: (1) the identification of the noncoding sequences that contribute to gene transcription and (2) the association of these sequences to the respective genes they control...
2016: Methods in Cell Biology
S Yang, C J Ott, M P Rossmann, M Superdock, L I Zon, Y Zhou
Zebrafish is an excellent genetic and developmental model for the study of vertebrate development and disease. Its ability to produce an abundance of transparent, externally developed embryos has facilitated large-scale genetic and chemical screens for the identification of critical genes and chemical factors that modulate developmental pathways. These studies can have profound implications for the diagnosis and treatment of a variety of human diseases. Recent advancements in molecular and genomic studies have provided valuable tools and resources for comprehensive and high-resolution analysis of epigenomes during cell specification and lineage differentiation throughout development...
2016: Methods in Cell Biology
Luca Giorgetti, Bryan R Lajoie, Ava C Carter, Mikael Attia, Ye Zhan, Jin Xu, Chong Jian Chen, Noam Kaplan, Howard Y Chang, Edith Heard, Job Dekker
X-chromosome inactivation (XCI) involves major reorganization of the X chromosome as it becomes silent and heterochromatic. During female mammalian development, XCI is triggered by upregulation of the non-coding Xist RNA from one of the two X chromosomes. Xist coats the chromosome in cis and induces silencing of almost all genes via its A-repeat region, although some genes (constitutive escapees) avoid silencing in most cell types, and others (facultative escapees) escape XCI only in specific contexts. A role for Xist in organizing the inactive X (Xi) chromosome has been proposed...
July 28, 2016: Nature
Laura J Scott, Michael R Erdos, Jeroen R Huyghe, Ryan P Welch, Andrew T Beck, Brooke N Wolford, Peter S Chines, John P Didion, Narisu Narisu, Heather M Stringham, D Leland Taylor, Anne U Jackson, Swarooparani Vadlamudi, Lori L Bonnycastle, Leena Kinnunen, Jouko Saramies, Jouko Sundvall, Ricardo D'Oliveira Albanus, Anna Kiseleva, John Hensley, Gregory E Crawford, Hui Jiang, Xiaoquan Wen, Richard M Watanabe, Timo A Lakka, Karen L Mohlke, Markku Laakso, Jaakko Tuomilehto, Heikki A Koistinen, Michael Boehnke, Francis S Collins, Stephen C J Parker
Type 2 diabetes (T2D) results from the combined effects of genetic and environmental factors on multiple tissues over time. Of the >100 variants associated with T2D and related traits in genome-wide association studies (GWAS), >90% occur in non-coding regions, suggesting a strong regulatory component to T2D risk. Here to understand how T2D status, metabolic traits and genetic variation influence gene expression, we analyse skeletal muscle biopsies from 271 well-phenotyped Finnish participants with glucose tolerance ranging from normal to newly diagnosed T2D...
2016: Nature Communications
Cornelis J Boogerd, Ivy Aneas, Noboru Sakabe, Ralph J Dirschinger, Quen J Cheng, Bin Zhou, Ju Chen, Marcelo A Nobrega, Sylvia M Evans
Mutations in the T-box transcription factor TBX20 are associated with multiple forms of congenital heart defects, including cardiac septal abnormalities, but our understanding of the contributions of endocardial TBX20 to heart development remains incomplete. Here, we investigated how TBX20 interacts with endocardial gene networks to drive the mesenchymal and myocardial movements that are essential for outflow tract and atrioventricular septation. Selective ablation of Tbx20 in murine endocardial lineages reduced the expression of extracellular matrix and cell migration genes that are critical for septation...
August 1, 2016: Journal of Clinical Investigation
André F Rendeiro, Christian Schmidl, Jonathan C Strefford, Renata Walewska, Zadie Davis, Matthias Farlik, David Oscier, Christoph Bock
Chronic lymphocytic leukaemia (CLL) is characterized by substantial clinical heterogeneity, despite relatively few genetic alterations. To provide a basis for studying epigenome deregulation in CLL, here we present genome-wide chromatin accessibility maps for 88 CLL samples from 55 patients measured by the ATAC-seq assay. We also performed ChIPmentation and RNA-seq profiling for ten representative samples. Based on the resulting data set, we devised and applied a bioinformatic method that links chromatin profiles to clinical annotations...
2016: Nature Communications
Jingyi Wu, Bo Huang, He Chen, Qiangzong Yin, Yang Liu, Yunlong Xiang, Bingjie Zhang, Bofeng Liu, Qiujun Wang, Weikun Xia, Wenzhi Li, Yuanyuan Li, Jing Ma, Xu Peng, Hui Zheng, Jia Ming, Wenhao Zhang, Jing Zhang, Geng Tian, Feng Xu, Zai Chang, Jie Na, Xuerui Yang, Wei Xie
In mammals, extensive chromatin reorganization is essential for reprogramming terminally committed gametes to a totipotent state during preimplantation development. However, the global chromatin landscape and its dynamics in this period remain unexplored. Here we report a genome-wide map of accessible chromatin in mouse preimplantation embryos using an improved assay for transposase-accessible chromatin with high throughput sequencing (ATAC-seq) approach with CRISPR/Cas9-assisted mitochondrial DNA depletion...
June 30, 2016: Nature
Christopher D Scharer, Emily L Blalock, Benjamin G Barwick, Robert R Haines, Chungwen Wei, Ignacio Sanz, Jeremy M Boss
Biobanking is a widespread practice for storing biological samples for future studies ranging from genotyping to RNA analysis. However, methods that probe the status of the epigenome are lacking. Here, the framework for applying the Assay for Transposase Accessible Sequencing (ATAC-seq) to biobanked specimens is described and was used to examine the accessibility landscape of naïve B cells from Systemic Lupus Erythematosus (SLE) patients undergoing disease flares. An SLE specific chromatin accessibility signature was identified...
2016: Scientific Reports
Pamela Milani, Renan Escalante-Chong, Brandon C Shelley, Natasha L Patel-Murray, Xiaofeng Xin, Miriam Adam, Berhan Mandefro, Dhruv Sareen, Clive N Svendsen, Ernest Fraenkel
In recent years, the assay for transposase-accessible chromatin using sequencing (ATAC-Seq) has become a fundamental tool of epigenomic research. However, it is difficult to perform this technique on frozen samples because freezing cells before extracting nuclei can impair nuclear integrity and alter chromatin structure, especially in fragile cells such as neurons. Our aim was to develop a protocol for freezing neuronal cells that is compatible with ATAC-Seq; we focused on a disease-relevant cell type, namely motor neurons differentiated from induced pluripotent stem cells (iMNs) from a patient affected by spinal muscular atrophy...
2016: Scientific Reports
Natsuhiko Kumasaka, Andrew J Knights, Daniel J Gaffney
No abstract text is available yet for this article.
April 2016: Nature Genetics
Songjoon Baek, Myong-Hee Sung
High-throughput sequencing technologies have made it possible for biologists to generate genome-wide profiles of chromatin features at the nucleotide resolution. Enzymes such as nucleases or transposes have been instrumental as a chromatin-probing agent due to their ability to target accessible chromatin for cleavage or insertion. On the scale of a few hundred base pairs, preferential action of the nuclear enzymes on accessible chromatin allows mapping of cell state-specific accessibility in vivo. Such accessible regions contain functionally important regulatory sites, including promoters and enhancers, which undergo active remodeling for cells adapting in a dynamic environment...
2016: Methods in Molecular Biology
Amanda M Ackermann, Zhiping Wang, Jonathan Schug, Ali Naji, Klaus H Kaestner
OBJECTIVE: Although glucagon-secreting α-cells and insulin-secreting β-cells have opposing functions in regulating plasma glucose levels, the two cell types share a common developmental origin and exhibit overlapping transcriptomes and epigenomes. Notably, destruction of β-cells can stimulate repopulation via transdifferentiation of α-cells, at least in mice, suggesting plasticity between these cell fates. Furthermore, dysfunction of both α- and β-cells contributes to the pathophysiology of type 1 and type 2 diabetes, and β-cell de-differentiation has been proposed to contribute to type 2 diabetes...
March 2016: Molecular Metabolism
Brandon Chin Sos, Ho-Lim Fung, Derek Rui Gao, Trina Faye Osothprarop, Amirali Kia, Molly Min He, Kun Zhang
Chromatin accessibility captures in vivo protein-chromosome binding status, and is considered an informative proxy for protein-DNA interactions. DNase I and Tn5 transposase assays require thousands to millions of fresh cells for comprehensive chromatin mapping. Applying Tn5 tagmentation to hundreds of cells results in sparse chromatin maps. We present a transposome hypersensitive sites sequencing assay for highly sensitive characterization of chromatin accessibility. Linear amplification of accessible DNA ends with in vitro transcription, coupled with an engineered Tn5 super-mutant, demonstrates improved sensitivity on limited input materials, and accessibility of small regions near distal enhancers, compared with ATAC-seq...
2016: Genome Biology
Xiaomin Bao, Adam J Rubin, Kun Qu, Jiajing Zhang, Paul G Giresi, Howard Y Chang, Paul A Khavari
BACKGROUND: Open chromatin regions are correlated with active regulatory elements in development and are dysregulated in diseases. The BAF (SWI/SNF) complex is essential for development, and has been demonstrated to remodel reconstituted chromatin in vitro and to control the accessibility of a few individual regions in vivo. However, it remains unclear where and how BAF controls the open chromatin landscape to regulate developmental processes, such as human epidermal differentiation. RESULTS: Using a novel "on-plate" ATAC-sequencing approach for profiling open chromatin landscapes with a low number of adherent cells, we demonstrate that the BAF complex is essential for maintaining 11...
2015: Genome Biology
Natsuhiko Kumasaka, Andrew J Knights, Daniel J Gaffney
When cellular traits are measured using high-throughput DNA sequencing, quantitative trait loci (QTLs) manifest as fragment count differences between individuals and allelic differences within individuals. We present RASQUAL (Robust Allele-Specific Quantitation and Quality Control), a new statistical approach for association mapping that models genetic effects and accounts for biases in sequencing data using a single, probabilistic framework. RASQUAL substantially improves fine-mapping accuracy and sensitivity relative to existing methods in RNA-seq, DNase-seq and ChIP-seq data...
February 2016: Nature Genetics
Claire Mazumdar, Ying Shen, Seethu Xavy, Feifei Zhao, Andreas Reinisch, Rui Li, M Ryan Corces, Ryan A Flynn, Jason D Buenrostro, Steven M Chan, Daniel Thomas, Julie L Koenig, Wan-Jen Hong, Howard Y Chang, Ravindra Majeti
Recurrent mutations in cohesin complex proteins have been identified in pre-leukemic hematopoietic stem cells and during the early development of acute myeloid leukemia and other myeloid malignancies. Although cohesins are involved in chromosome separation and DNA damage repair, cohesin complex functions during hematopoiesis and leukemic development are unclear. Here, we show that mutant cohesin proteins block differentiation of human hematopoietic stem and progenitor cells (HSPCs) in vitro and in vivo and enforce stem cell programs...
December 3, 2015: Cell Stem Cell
Karel van Duijvenboden, Bouke A de Boer, Nicolas Capon, Jan M Ruijter, Vincent M Christoffels
Regulatory DNA elements, short genomic segments that regulate gene expression, have been implicated in developmental disorders and human disease. Despite this clinical urgency, only a small fraction of the regulatory DNA repertoire has been confirmed through reporter gene assays. The overall success rate of functional validation of candidate regulatory elements is low. Moreover, the number and diversity of datasets from which putative regulatory elements can be identified is large and rapidly increasing. We generated a flexible and user-friendly tool to integrate the information from different types of genomic datasets, e...
March 18, 2016: Nucleic Acids Research
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