Publication
Finn EH et al. (2019)Extensive Heterogeneity and Intrinsic Variation in Spatial Genome Organization.

current
   October 11th, 2017 at 9:36pm

Overview


Abstract

Several general principles of global 3D genome organization have recently been established, including non-random positioning of chromosomes and genes in the cell nucleus, distinct chromatin compartments, and topologically associating domains (TADs). However, the extent and nature of cell-to-cell and cell-intrinsic variability in genome architecture are still poorly characterized. Here, we systematically probe heterogeneity in genome organization. High-throughput optical mapping of several hundred intra-chromosomal interactions in individual human fibroblasts demonstrates low association frequencies, which are determined by genomic distance, higher-order chromatin architecture, and chromatin environment. The structure of TADs is variable between individual cells, and inter-TAD associations are common. Furthermore, single-cell analysis reveals independent behavior of individual alleles in single nuclei. Our observations reveal extensive variability and heterogeneity in genome organization at the level of individual alleles and demonstrate the coexistence of a broad spectrum of genome configurations in a cell population.

Authors

Finn EH  •  Pegoraro G  •  Brandao HB  •  Valton AL  •  Oomen ME  •  Dekker J  •  Mirny L  •  Misteli T

Link

https://www.ncbi.nlm.nih.gov/pubmed/30799036


Journal

Cell

PMID:30799036

Published

February 1st, 2019


Project Summary

Finn et al systematically probed the heterogeneity in genome organization in human fibroblasts by combining high-resolution Hi-C datasets and high-throughput genome imaging. High-throughput Imaging Position MAPing (HIPMap) based on high-throughput fluorescence in situ hybridization (hiFISH) was used to systematically determine the spatial position and distances between combinations of genomic interaction pairs identified by Hi-C.

Dilution Hi-C experiments were performed with HFF-hTERT cells, and various loci were chosen on chromosomes 1, 17 and 18 to test distances of different pairs of loci with high-throughput DNA-FISH (HIPMap). Interaction of TADs was also probed on chromosome 4. Here you can find a summary of the experiments performed.

Microcopy Dataset

Aim

Target List

DNA-FISH on Chr1

Testing different Hi-C frequencies

Targets on Chr1

DNA-FISH on Chr17

Testing different Hi-C frequencies

Targets on Chr17

DNA-FISH on Chr18

Testing different Hi-C frequencies

Targets on Chr18

DNA-FISH on Chr1 and 17

Testing different Hi-C frequencies

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DNA-FISH on Chr4

Testing TAD interaction

Targets on Chr4

Pairwise Probe Locations

The loci selected for imaging are overlaid on the Hi-C data for HFF-HFF-hTERT cells.

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Data Availability

  • Hi-C data:
    • The experiments were performed in 4 techincal replicates (4DNES9L4AK6Q).
    • Data files for contact lists and contact matrices based on the 4DN Hi-C pipeline are linked to the Replicate Experiment Set.
  • HIPMap data:
    • Raw image files are available for download for a subset of the HIPMap experiments. These images can be also viewed online by following the links to the OMERO viewer for each file. Please contact support@4dnucleome.org if you are interested in the complete data set.
    • For each experiment individual distance measurements can be found under processed files tab of linked datasets.
    • Results from all of the microscopy results is summarized in this tsv file
  • All the data on the portal is immediately accessible via the 4DN JupyterHub. The code to reproduce Figure 1F of Finn et. al. is provided in the examples folder, as one of the sample ipython notebook files.

 



Figure produced on 4DN Jupyter Hub, with notebook examples/Finn et al, Microscopy and HiC data overlaid