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THUNDER: A reference-free deconvolution method to infer cell type proportions from bulk Hi-C data.

Bryce Rowland1, Ruth Huh1, Zoey Hou2

  • 1Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.

Plos Genetics
|March 8, 2022
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Summary

We developed THUNDER, a new unsupervised method to accurately determine cell type proportions in bulk Hi-C data. This approach improves analysis of 3D genome organization by accounting for cellular heterogeneity.

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Area of Science:

  • Genomics
  • Computational Biology
  • Epigenetics

Background:

  • Bulk Hi-C data offers population-averaged 3D chromatin contact information.
  • Analyzing heterogeneous bulk samples requires controlling for varying cell type proportions.
  • Accurate cell type deconvolution is crucial for robust downstream Hi-C analyses.

Purpose of the Study:

  • To introduce THUNDER, a novel unsupervised deconvolution method for inferring cell type composition from bulk Hi-C data.
  • To evaluate THUNDER's accuracy and robustness against existing methods using simulations and real-world data.
  • To provide a tool for analyzing cell-type-specific chromatin interactions.

Main Methods:

  • Developed the Two-step Hi-c UNsupervised DEconvolution appRoach (THUNDER).
  • Validated THUNDER using simulated data derived from single-cell Hi-C (scHi-C) datasets.
  • Applied THUNDER to Hi-C data from adult human cortex samples.

Main Results:

  • THUNDER demonstrated superior accuracy in estimating cell type proportions compared to reference-free methods (TOAST, NMF).
  • THUNDER showed greater robustness than reference-dependent methods like MuSiC.
  • Successfully applied THUNDER to identify cell-type-specific interactions in human cortex Hi-C data.

Conclusions:

  • THUNDER is an effective unsupervised tool for deconvolution of cell type composition in bulk Hi-C data.
  • The method facilitates more valid and powerful downstream analyses, such as differential chromatin organization studies.
  • THUNDER's estimated contact profiles offer a framework for exploring chromatin interactome cell-type-specificity.