Dataset Information

Impact of data resolution on three-dimensional structure inference methods.

ABSTRACT: Assays that are capable of detecting genome-wide chromatin interactions have produced massive amount of data and led to great understanding of the chromosomal three-dimensional (3D) structure. As technology becomes more sophisticated, higher-and-higher resolution data are being produced, going from the initial 1 Megabases (Mb) resolution to the current 10 Kilobases (Kb) or even 1 Kb resolution. The availability of genome-wide interaction data necessitates development of analytical methods to recover the underlying 3D spatial chromatin structure, but challenges abound. Most of the methods were proposed for analyzing data at low resolution (1 Mb). Their behaviors are thus unknown for higher resolution data. For such data, one of the key features is the high proportion of "0" contact counts among all available data, in other words, the excess of zeros.To address the issue of excess of zeros, in this paper, we propose a truncated Random effect EXpression (tREX) method that can handle data at various resolutions. We then assess the performance of tREX and a number of leading existing methods for recovering the underlying chromatin 3D structure. This was accomplished by creating in-silico data to mimic multiple levels of resolution and submit the methods to a "stress test". Finally, we applied tREX and the comparison methods to a Hi-C dataset for which FISH measurements are available to evaluate estimation accuracy.The proposed tREX method achieves consistently good performance in all 30 simulated settings considered. It is not only robust to resolution level and underlying parameters, but also insensitive to model misspecification. This conclusion is based on observations made in terms of 3D structure estimation accuracy and preservation of topologically associated domains. Application of the methods to the human lymphoblastoid cell line data on chromosomes 14 and 22 further substantiates the superior performance of tREX: the constructed 3D structure from tREX is consistent with the FISH measurements, and the corresponding distances predicted by tREX have higher correlation with the FISH measurements than any of the comparison methods.An open-source R-package is available at http://www.stat.osu.edu/~statgen/Software/tRex.

SUBMITTER: Park J

PROVIDER: S-EPMC4744395 | biostudies-literature | 2016 Feb

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Impact of data resolution on three-dimensional structure inference methods.

Park Jincheol J Lin Shili S

BMC bioinformatics 20160206

<h4>Background</h4>Assays that are capable of detecting genome-wide chromatin interactions have produced massive amount of data and led to great understanding of the chromosomal three-dimensional (3D) structure. As technology becomes more sophisticated, higher-and-higher resolution data are being produced, going from the initial 1 Megabases (Mb) resolution to the current 10 Kilobases (Kb) or even 1 Kb resolution. The availability of genome-wide interaction data necessitates development of analyt ...[more]

PMID: 26852142

Similar Datasets

Project description:BackgroundThe human glomerulus is the primary filtration unit of the kidney, and contains the Glomerular Filtration Barrier (GFB). The GFB had been thought to comprise 3 layers - the endothelium, the basement membrane and the podocyte foot processes. However, recent studies have suggested that at least two additional layers contribute to the function of the GFB, the endothelial glycocalyx on the vascular side, and the sub-podocyte space on the urinary side. To investigate the structure of these additional layers is difficult as it requires three-dimensional reconstruction of delicate sub-microscopic (<1 μm) cellular and extracellular elements.MethodsHere we have combined three different advanced electron microscopic techniques that cover multiple orders of magnitude of volume sampled, with a novel staining methodology (Lanthanum Dysprosium Glycosaminoglycan adhesion, or LaDy GAGa), to determine the structural basis of these two additional layers. Serial Block Face Scanning Electron Microscopy (SBF-SEM) was used to generate a 3-D image stack with a volume of a 5.3 x 105 μm3 volume of a whole kidney glomerulus (13% of glomerular volume). Secondly, Focused Ion Beam milling Scanning Electron Microscopy (FIB-SEM) was used to image a filtration region (48 μm3 volume). Lastly Transmission Electron Tomography (Tom-TEM) was performed on a 0.3 μm3 volume to identify the fine structure of the glycocalyx.ResultsTom-TEM clearly showed 20 nm fibre spacing in the glycocalyx, within a limited field of view. FIB-SEM demonstrated, in a far greater field of view, how the glycocalyx structure related to fenestrations and the filtration slits, though without the resolution of TomTEM. SBF-SEM was able to determine the extent of the sub-podocyte space and glycocalyx coverage, without additional heavy metal staining. Neither SBF- nor FIB-SEM suffered the anisotropic shrinkage under the electron beam that is seen with Tom-TEM.ConclusionsThese images demonstrate that the three dimensional structure of the GFB can be imaged, and investigated from the whole glomerulus to the fine structure of the glycocalyx using three dimensional electron microscopy techniques. This should allow the identification of structural features regulating physiology, and their disruption in pathological states, aiding the understanding of kidney disease.

Dataset Information

Impact of data resolution on three-dimensional structure inference methods.

Publications

Impact of data resolution on three-dimensional structure inference methods.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets