Population Variation and Genetic Control of Modular Chromatin Architecture in Humans

Waszak, Sebastian M.; Delaneau, Olivier; Gschwind, Andreas R.; Kilpinen, Helena; Raghav, Sunil K.; Witwicki, Robert M.; Orioli, Andrea; Wiederkehr, Michael R.; Panousis, Nikolaos; Yurovsky, Alisa; Romano-Palumbo, Luciana; Planchon, Alexandra; Bielser, Deborah; Padioleau, Ismaël; Udin, Gilles; Thurnheer, Sarah; Hacker, David L.; Hernandez, Nouria; Reymond, Alexandre; Deplancke, Bart; Dermitzakis, Emmanouil T.

doi:10.1016/j.cell.2015.08.001

Cited by 212 publications

(301 citation statements)

References 48 publications

(64 reference statements)

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“…1B), which represent a separation of PICs and PCs across a genome at near-single base-pair resolution. Although PIC and pause separation was reported by Quinodoz et al (Quinodoz et al 2014;Waszak et al 2015), we find the data are inconsistent with such locations (Supplemental Fig. S6).…”

Section: Spatial Separation Of Pics and Pcscontrasting

confidence: 56%

Genome-wide uniformity of human ‘open’ pre-initiation complexes

Lai

Pugh

2016

Genome Res.

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Transcription of protein-coding and noncoding DNA occurs pervasively throughout the mammalian genome. Their sites of initiation are generally inferred from transcript 5 ′ ends and are thought to be either locally dispersed or focused. How these two modes of initiation relate is unclear. Here, we apply permanganate treatment and chromatin immunoprecipitation (PIPseq) of initiation factors to identify the precise location of melted DNA separately associated with the preinitiation complex (PIC) and the adjacent paused complex (PC). This approach revealed the two known modes of transcription initiation. However, in contrast to prevailing views, they co-occurred within the same promoter region: initiation originating from a focused PIC, and broad nucleosome-linked initiation. PIP-seq allowed transcriptional orientation of Pol II to be determined, which may be useful near promoters where sufficient sense/anti-sense transcript mapping information is lacking. PIP-seq detected divergently oriented Pol II at both coding and noncoding promoters, as well as at enhancers. Their occupancy levels were not necessarily coupled in the two orientations. DNA sequence and shape analysis of initiation complex sites suggest that both sequence and shape contribute to specificity, but in a context-restricted manner. That is, initiation sites have the locally "best" initiator (INR) sequence and/or shape. These findings reveal a common core to pervasive Pol II initiation throughout the human genome.

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Section: Spatial Separation Of Pics and Pcscontrasting

confidence: 56%

Genome-wide uniformity of human ‘open’ pre-initiation complexes

Lai

Pugh

2016

Genome Res.

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“…We compared the read counts across all possible human-centric species × species and group × group pairwise comparisons. This approach provides a quantitative assessment of histone modification profiles across species, while avoiding issues arising from experimental variables that may confound peak calling (Waszak et al 2015). An analysis of human and marmoset, the latter being the species with the smallest number of peaks called in Figure 1.…”

Section: Resultsmentioning

confidence: 99%

Transposable elements are the primary source of novelty in primate gene regulation

et al. 2017

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Gene regulation shapes the evolution of phenotypic diversity. We investigated the evolution of liver promoters and enhancers in six primate species using ChIP-seq (H3K27ac and H3K4me1) to profile cis-regulatory elements (CREs) and using RNAseq to characterize gene expression in the same individuals. To quantify regulatory divergence, we compared CRE activity across species by testing differential ChIP-seq read depths directly measured for orthologous sequences. We show that the primate regulatory landscape is largely conserved across the lineage, with 63% of the tested human liver CREs showing similar activity across species. Conserved CRE function is associated with sequence conservation, proximity to coding genes, cell-type specificity, and transcription factor binding. Newly evolved CREs are enriched in immune response and neurodevelopmental functions. We further demonstrate that conserved CREs bind master regulators, suggesting that while CREs contribute to species adaptation to the environment, core functions remain intact. Newly evolved CREs are enriched in young transposable elements (TEs), including Long-Terminal-Repeats (LTRs) and SINE-VNTR-Alus (SVAs), that significantly affect gene expression. Conversely, only 16% of conserved CREs overlap TEs. We tested the cis-regulatory activity of 69 TE subfamilies by luciferase reporter assays, spanning all major TE classes, and showed that 95.6% of tested TEs can function as either transcriptional activators or repressors. In conclusion, we demonstrated the critical role of TEs in primate gene regulation and illustrated potential mechanisms underlying evolutionary divergence among the primate species through the noncoding genome.

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“…In line with this, gene silencing on the inactive X chromosome in female mammalian cells was shown to also occur at the level of TADs, and gene clusters of escapees that do not become silenced correlate with TADs (Marks et al 2015). Further strong evidence for TADs being the functional units of the genome came from two recent studies that established the existence of the long-range impact of genetic variation on histone modifications elsewhere on chromosomes: Both studies showed that such communication takes place in the context of TADs (Grubert et al 2015;Waszak et al 2015). TADs are formed during early G1 of the cell cycle, concomitant with the establishment of the replication timing program (Dileep et al 2015), and TAD boundaries often coincide with replication domain boundaries (Pope et al 2014).…”

Section: Tads and Sub-tadsmentioning

confidence: 98%

The second decade of 3C technologies: detailed insights into nuclear organization

2016

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The relevance of three-dimensional (3D) genome organization for transcriptional regulation and thereby for cellular fate at large is now widely accepted. Our understanding of the fascinating architecture underlying this function is based on microscopy studies as well as the chromosome conformation capture (3C) methods, which entered the stage at the beginning of the millennium. The first decade of 3C methods rendered unprecedented insights into genome topology. Here, we provide an update of developments and discoveries made over the more recent years. As we discuss, established and newly developed experimental and computational methods enabled identification of novel, functionally important chromosome structures. Regulatory and architectural chromatin loops throughout the genome are being cataloged and compared between cell types, revealing tissue invariant and developmentally dynamic loops. Architectural proteins shaping the genome were disclosed, and their mode of action is being uncovered. We explain how more detailed insights into the 3D genome increase our understanding of transcriptional regulation in development and misregulation in disease. Finally, to help researchers in choosing the approach best tailored for their specific research question, we explain the differences and commonalities between the various 3C-derived methods.

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Population Variation and Genetic Control of Modular Chromatin Architecture in Humans

Cited by 212 publications

References 48 publications

Genome-wide uniformity of human ‘open’ pre-initiation complexes

Genome-wide uniformity of human ‘open’ pre-initiation complexes

Transposable elements are the primary source of novelty in primate gene regulation

The second decade of 3C technologies: detailed insights into nuclear organization

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