Chromatin state signatures associated with tissue-specific gene expression and enhancer activity in the embryonic limb
Justin Cotney,Jing Leng,Sunghee Oh,Laura E. DeMare,Steven K. Reilly,Mark Gerstein,James P. Noonan +6 more
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TLDR
The results establish histone modification profiling as a tool for developmental enhancer discovery, and suggest that enhancers maintain an open chromatin state in multiple embryonic tissues independent of their activity level.Abstract:
.The regulatory elements that direct tissue-specific gene expression in the developing mammalian embryo remain largely unknown. Although chromatin profiling has proven to be a powerful method for mapping regulatory sequences in cultured cells, chromatin states characteristic of active developmental enhancers have not been directly identified in embryonic tissues. Here we use whole-transcriptome analysis coupled with genome-wide profiling of H3K27ac and H3K27me3 to map chromatin states and enhancers in mouse embryonic forelimb and hindlimb. We show that gene-expression differences between forelimb and hindlimb, and between limb and other embryonic cell types, are correlated with tissue-specific H3K27ac signatures at promoters and distal sites. Using H3K27ac profiles, we identified 28,377 putative enhancers, many of which are likely to be limb specific based on strong enrichment near genes highly expressed in the limb and comparisons with tissue-specific EP300 sites and known enhancers. We describe a chromatin state signature associated with active developmental enhancers, defined by high levels of H3K27ac marking, nucleosome displacement, hypersensitivity to sonication, and strong depletion of H3K27me3. We also find that some developmental enhancers exhibit components of this signature, including hypersensitivity, H3K27ac enrichment, and H3K27me3 depletion, at lower levels in tissues in which they are not active. Our results establish histone modification profiling as a tool for developmental enhancer discovery, and suggest that enhancers maintain an open chromatin state in multiple embryonic tissues independent of their activity level. [Supplemental material is available for this article.]read more
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Disruptions of Topological Chromatin Domains Cause Pathogenic Rewiring of Gene-Enhancer Interactions
Darío G. Lupiáñez,Darío G. Lupiáñez,Katerina Kraft,Katerina Kraft,Verena Heinrich,Peter Krawitz,Peter Krawitz,Francesco Brancati,Eva Klopocki,Denise Horn,Hülya Kayserili,John M. Opitz,Renata Laxova,Fernando Santos-Simarro,Fernando Santos-Simarro,Brigitte Gilbert-Dussardier,Lars Wittler,Marina Borschiwer,Stefan A. Haas,Marco Osterwalder,Martin Franke,Martin Franke,Bernd Timmermann,Jochen Hecht,Jochen Hecht,Malte Spielmann,Malte Spielmann,Axel Visel,Axel Visel,Axel Visel,Stefan Mundlos,Stefan Mundlos +31 more
TL;DR: The results demonstrate the functional importance of TADs for orchestrating gene expression via genome architecture and indicate criteria for predicting the pathogenicity of human structural variants, particularly in non-coding regions of the human genome.
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Genomic Analysis of Non-NF2 Meningiomas Reveals Mutations in TRAF7, KLF4, AKT1, and SMO
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TL;DR: Genetic analysis of 300 meningiomas, the most common primary brain tumors, leads to the discovery of mutations in TRAF7, a proapoptotic E3 ubiquitin ligase, in nearly one-fourth of all mening iomas, suggesting avenues for targeted therapeutics.
Journal ArticleDOI
Rapid and Pervasive Changes in Genome-wide Enhancer Usage during Mammalian Development
Alexander Nord,Matthew J. Blow,Matthew J. Blow,Catia Attanasio,Jennifer A. Akiyama,Amy Holt,Roya Hosseini,Sengthavy Phouanenavong,Ingrid Plajzer-Frick,Malak Shoukry,Veena Afzal,John L.R. Rubenstein,Edward M. Rubin,Edward M. Rubin,Len A. Pennacchio,Len A. Pennacchio,Axel Visel,Axel Visel,Axel Visel +18 more
TL;DR: The dynamic enhancer activities uncovered in this study illuminate rapid and pervasive temporal in vivo changes in enhancer usage that underlie processes central to development and disease.
Journal ArticleDOI
Epigenomic Annotation of Enhancers Predicts Transcriptional Regulators of Human Neural Crest
Alvaro Rada-Iglesias,Ruchi Bajpai,Sara L. Prescott,Samantha A. Brugmann,Tomek Swigut,Joanna Wysocka +5 more
TL;DR: This work coupled a hESC differentiation model with genome-wide profiling of histone modifications and of coactivator and transcription factor occupancy to annotate and characterize cis-regulatory elements utilized by the human NCC and provides global insights into human NC chromatin landscapes.
Journal ArticleDOI
Methylation QTLs Are Associated with Coordinated Changes in Transcription Factor Binding, Histone Modifications, and Gene Expression Levels
Nicholas E. Banovich,Xun Lan,Graham McVicker,Bryce van de Geijn,Jacob F. Degner,John D. Blischak,Julien Roux,Jonathan K. Pritchard,Yoav Gilad +8 more
TL;DR: It is found that SNPs that change predicted TF binding affinities are significantly enriched for associations with DNA methylation at nearby CpGs, suggesting that genetic variants may lead to coordinated molecular changes in all of these regulatory phenotypes.
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