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An atlas of lamina-associated chromatin across twelve human cell types reveals an intermediate chromatin subtype

View ORCID ProfileKathleen C. Keough, View ORCID ProfileParisha P. Shah, View ORCID ProfileKetrin Gjoni, View ORCID ProfileGarrett T. Santini, Nadeera M. Wickramasinghe, Carolyn E. Dundes, View ORCID ProfileAshley Karnay, Angela Chen, Rachel E.A. Salomon, Patrick J. Walsh, Son C. Nguyen, View ORCID ProfileSean Whalen, Eric F. Joyce, Kyle M. Loh, Nicole Dubois, View ORCID ProfileKatherine S. Pollard, View ORCID ProfileRajan Jain
doi: https://doi.org/10.1101/2020.07.23.218768
Kathleen C. Keough
aUniversity of California, San Francisco, CA 94117, USA
bGladstone Institute of Data Science and Biotechnology, San Francisco, CA 94158, USA
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  • ORCID record for Kathleen C. Keough
Parisha P. Shah
cDepartments of Medicine and Cell and Developmental Biology, Penn CVI, Penn Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104
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Ketrin Gjoni
aUniversity of California, San Francisco, CA 94117, USA
bGladstone Institute of Data Science and Biotechnology, San Francisco, CA 94158, USA
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Garrett T. Santini
cDepartments of Medicine and Cell and Developmental Biology, Penn CVI, Penn Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104
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Nadeera M. Wickramasinghe
dDepartment of Cell, Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029
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Carolyn E. Dundes
eDepartment of Developmental Biology and Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305 USA
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Ashley Karnay
cDepartments of Medicine and Cell and Developmental Biology, Penn CVI, Penn Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104
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Angela Chen
eDepartment of Developmental Biology and Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305 USA
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Rachel E.A. Salomon
eDepartment of Developmental Biology and Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305 USA
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Patrick J. Walsh
fDepartment of Genetics, Penn Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104
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Son C. Nguyen
fDepartment of Genetics, Penn Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104
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Sean Whalen
bGladstone Institute of Data Science and Biotechnology, San Francisco, CA 94158, USA
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Eric F. Joyce
fDepartment of Genetics, Penn Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104
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Kyle M. Loh
eDepartment of Developmental Biology and Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305 USA
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Nicole Dubois
dDepartment of Cell, Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029
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Katherine S. Pollard
aUniversity of California, San Francisco, CA 94117, USA
bGladstone Institute of Data Science and Biotechnology, San Francisco, CA 94158, USA
gChan Zuckerberg Biohub, San Francisco, CA 94158, USA
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  • For correspondence: kpollard@gladstone.ucsf.edu jainr@pennmedicine.upenn.edu
Rajan Jain
cDepartments of Medicine and Cell and Developmental Biology, Penn CVI, Penn Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104
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  • For correspondence: kpollard@gladstone.ucsf.edu jainr@pennmedicine.upenn.edu
  • Abstract
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Abstract

Association of chromatin with lamin proteins at the nuclear periphery has emerged as a potential mechanism to coordinate cell type-specific gene expression and maintain cellular identity via gene silencing. Unlike many histone modifications and chromatin-associated proteins, lamin-associated domains (LADs) have yet to be mapped genome-wide in a diverse panel of human cell types, which has limited our understanding of the role peripheral chromatin plays in development and disease. To address this gap, we mapped LAMIN B1 (LB1) across twelve human cell types encompassing pluripotent stem cells, intermediate progenitors, and differentiated cells from all three germ layers. Integrative analyses of this atlas of peripheral chromatin with publicly available genomic data, as well as gene expression and repressive histone maps generated for this study, revealed that in all twelve cellular contexts lamin-associated chromatin is organized into at least two subtypes defined by differences in LB1 occupancy, gene expression, chromatin accessibility, transposable elements, replication timing, and radial positioning. Most genes gain or lose LB1 occupancy consistent with their cell type along developmental trajectories; however, we also identified examples where the enhancer, but not the gene body and promoter, change LAD state. Imaging of fluorescently labeled DNA in single cells validated these transitions and showed intermediate radial positioning of LADs that are gene dense, relatively accessible, and dynamic across development. This atlas represents the largest resource to date for peripheral chromatin organization studies.

Competing Interest Statement

K.K. is currently an employee of FaunaBio. A.C. is currently an employee of Orca Bio. K.S.P. is a consultant for Tenaya Therapeutics.

  • Abbreviations

    ChIP
    chromatin immunoprecipitation
    ESC
    embryonic stem cell
    FISH
    fluorescence in situ hybridization
    GO
    gene ontology
    H3K9me2
    dimethylated histone H3 lysine 9
    HMM
    Hidden Markov Model
    IQR
    interquartile range
    kb
    kilobases (1,000 basepairs)
    KDD
    K9-dimethyl domain, or H3K9me2-associated domain
    LAD
    lamina-associated domain
    LB1
    LAMIN B1
    Mb
    megabases (1,000,000 basepairs)
    qRT-PCR
    quantitative reverse transcription PCR
    T1-KDD
    Type 1 KDD
    T1-LAD
    Type 1 LAD
    T2-KDD
    Type 2 KDD
    T2-LAD
    Type 2 LAD
    TPM
    transcripts per million reads
  • Copyright 
    The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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    An atlas of lamina-associated chromatin across twelve human cell types reveals an intermediate chromatin subtype
    Kathleen C. Keough, Parisha P. Shah, Ketrin Gjoni, Garrett T. Santini, Nadeera M. Wickramasinghe, Carolyn E. Dundes, Ashley Karnay, Angela Chen, Rachel E.A. Salomon, Patrick J. Walsh, Son C. Nguyen, Sean Whalen, Eric F. Joyce, Kyle M. Loh, Nicole Dubois, Katherine S. Pollard, Rajan Jain
    bioRxiv 2020.07.23.218768; doi: https://doi.org/10.1101/2020.07.23.218768
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    An atlas of lamina-associated chromatin across twelve human cell types reveals an intermediate chromatin subtype
    Kathleen C. Keough, Parisha P. Shah, Ketrin Gjoni, Garrett T. Santini, Nadeera M. Wickramasinghe, Carolyn E. Dundes, Ashley Karnay, Angela Chen, Rachel E.A. Salomon, Patrick J. Walsh, Son C. Nguyen, Sean Whalen, Eric F. Joyce, Kyle M. Loh, Nicole Dubois, Katherine S. Pollard, Rajan Jain
    bioRxiv 2020.07.23.218768; doi: https://doi.org/10.1101/2020.07.23.218768

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