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Single-cell analysis of chromatin and expression reveals age- and sex-associated alterations in the human heart

View ORCID ProfileDavid F Read, View ORCID ProfileGregory T Booth, View ORCID ProfileRiza M Daza, View ORCID ProfileDana L Jackson, View ORCID ProfileRula Green Gladden, View ORCID ProfileSanjay R Srivatsan, View ORCID ProfileBrent Ewing, View ORCID ProfileJennifer M Franks, View ORCID ProfileCailyn H Spurrell, View ORCID ProfileAnne Roshella Gomes, View ORCID ProfileDiana O’Day, View ORCID ProfileAishwarya A Gogate, View ORCID ProfileBeth K Martin, View ORCID ProfileLea Starita, Yiing Lin, View ORCID ProfileJay Shendure, View ORCID ProfileShin Lin, View ORCID ProfileCole Trapnell
doi: https://doi.org/10.1101/2022.07.12.496461
David F Read
1Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA
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Gregory T Booth
1Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA
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  • ORCID record for Gregory T Booth
Riza M Daza
1Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA
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Dana L Jackson
1Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA
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Rula Green Gladden
1Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA
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Sanjay R Srivatsan
1Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA
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Brent Ewing
1Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA
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Jennifer M Franks
1Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA
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Cailyn H Spurrell
2Brotman Baty Institute for Precision Medicine, Seattle, WA 98195, USA
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Anne Roshella Gomes
2Brotman Baty Institute for Precision Medicine, Seattle, WA 98195, USA
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Diana O’Day
2Brotman Baty Institute for Precision Medicine, Seattle, WA 98195, USA
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Aishwarya A Gogate
2Brotman Baty Institute for Precision Medicine, Seattle, WA 98195, USA
3Seattle Children’s Research Institute, Seattle, WA 98101, USA
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Beth K Martin
1Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA
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Lea Starita
1Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA
2Brotman Baty Institute for Precision Medicine, Seattle, WA 98195, USA
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Yiing Lin
4Department of Surgery, Washington University, St Louis, MO 63110
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Jay Shendure
1Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA
3Seattle Children’s Research Institute, Seattle, WA 98101, USA
5Howard Hughes Medical Institute, Seattle, WA 98195, USA
6Allen Discovery Center for Cell Lineage Tracing, Seattle, WA 98195, USA
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  • For correspondence: shendure@gmail.com shinlin@cardiology.washington.edu coletrap@uw.edu
Shin Lin
7University of Washington School of Medicine, Division of Cardiology, Seattle, WA 98195, USA
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  • For correspondence: shendure@gmail.com shinlin@cardiology.washington.edu coletrap@uw.edu
Cole Trapnell
1Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA
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  • For correspondence: shendure@gmail.com shinlin@cardiology.washington.edu coletrap@uw.edu
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Abstract

Sex differences and age-related changes in the human heart at the tissue, cell, and molecular level have been well-documented and many may be relevant for cardiovascular disease. However, how molecular programs within individual cell types vary across individuals by age and sex remains poorly characterized. To better understand this variation, we performed single-nucleus combinatorial indexing (sci) ATAC- and RNA-Seq in human heart samples from nine donors. We identify hundreds of differentially expressed genes by age and sex. Sex dependent alterations include pathways such as TGFβ signaling and metabolic shifts by sex, evident in both transcriptional alterations and differing presence of transcription factor (TF) motifs in accessible chromatin. Age was associated with changes such as immune activation-related transcriptional and chromatin accessibility differences, as well as changes in the relative proportion of cardiomyocytes, neurons, and perivascular cells. In addition, we compare our adult-derived ATAC-Seq profiles to analogous fetal cell types to identify putative developmental-stage-specific regulatory factors. Finally, we train predictive models of cell-type-specific RNA expression levels utilizing ATAC-Seq profiles to link distal regulatory sequences to promoters, quantifying the predictive value of a simple TF-to-expression regulatory grammar and identifying cell-type-specific TFs.

Competing Interest Statement

C.T. is a SAB member, consultant and/or co-founder of Algen Biotechnologies, Altius Therapeutics, and Scale Biosciences. J.S. is a scientific advisory board member, consultant and/or cofounder of Cajal Neuroscience, Guardant Health, Maze Therapeutics, Camp4 Therapeutics, Phase Genomics, Adaptive Biotechnologies and Scale Biosciences.

Footnotes

  • The "Acknowledgments" section has been updated to include grant numbers for two CZI awards, as well as to correct the grant number of a U54 grant that supported this work. Additionally, the second author has been edited to be listed as "Gregory T Booth", instead of "Greg Booth".

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-ND 4.0 International license.
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Posted July 19, 2022.
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Single-cell analysis of chromatin and expression reveals age- and sex-associated alterations in the human heart
David F Read, Gregory T Booth, Riza M Daza, Dana L Jackson, Rula Green Gladden, Sanjay R Srivatsan, Brent Ewing, Jennifer M Franks, Cailyn H Spurrell, Anne Roshella Gomes, Diana O’Day, Aishwarya A Gogate, Beth K Martin, Lea Starita, Yiing Lin, Jay Shendure, Shin Lin, Cole Trapnell
bioRxiv 2022.07.12.496461; doi: https://doi.org/10.1101/2022.07.12.496461
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Single-cell analysis of chromatin and expression reveals age- and sex-associated alterations in the human heart
David F Read, Gregory T Booth, Riza M Daza, Dana L Jackson, Rula Green Gladden, Sanjay R Srivatsan, Brent Ewing, Jennifer M Franks, Cailyn H Spurrell, Anne Roshella Gomes, Diana O’Day, Aishwarya A Gogate, Beth K Martin, Lea Starita, Yiing Lin, Jay Shendure, Shin Lin, Cole Trapnell
bioRxiv 2022.07.12.496461; doi: https://doi.org/10.1101/2022.07.12.496461

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