RT Journal Article
SR Electronic
T1 Single-cell analysis of chromatin and expression reveals age- and sex-associated alterations in the human heart
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2022.07.12.496461
DO 10.1101/2022.07.12.496461
A1 David F Read
A1 Gregory T Booth
A1 Riza M Daza
A1 Dana L Jackson
A1 Rula Green Gladden
A1 Sanjay R Srivatsan
A1 Brent Ewing
A1 Jennifer M Franks
A1 Cailyn H Spurrell
A1 Anne Roshella Gomes
A1 Diana O’Day
A1 Aishwarya A Gogate
A1 Beth K Martin
A1 Lea Starita
A1 Yiing Lin
A1 Jay Shendure
A1 Shin Lin
A1 Cole Trapnell
YR 2022
UL http://biorxiv.org/content/early/2022/07/19/2022.07.12.496461.abstract
AB 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 StatementC.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.