Chromatin Potential Identified by Shared Single-Cell Profiling of RNA and Chromatin

Sai Ma; Bing Zhang; Lindsay M LaFave; Andrew S Earl; Zachary Chiang; Yan Hu; Jiarui Ding; Alison Brack; Vinay K Kartha; Tristan Tay; Travis Law; Caleb Lareau; Ya-Chieh Hsu; Aviv Regev; Jason D Buenrostro

doi:10.1016/j.cell.2020.09.056

Chromatin Potential Identified by Shared Single-Cell Profiling of RNA and Chromatin

Cell. 2020 Nov 12;183(4):1103-1116.e20. doi: 10.1016/j.cell.2020.09.056. Epub 2020 Oct 23.

Authors

Sai Ma¹, Bing Zhang², Lindsay M LaFave³, Andrew S Earl², Zachary Chiang², Yan Hu², Jiarui Ding⁴, Alison Brack², Vinay K Kartha², Tristan Tay², Travis Law⁴, Caleb Lareau⁵, Ya-Chieh Hsu², Aviv Regev⁶, Jason D Buenrostro⁷

Affiliations

¹ Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Biology and Koch Institute, Massachusetts Institute of Technology, Cambridge, MA 02142, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.
² Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.
³ Department of Biology and Koch Institute, Massachusetts Institute of Technology, Cambridge, MA 02142, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.
⁴ Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
⁵ Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.
⁶ Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Biology and Koch Institute, Massachusetts Institute of Technology, Cambridge, MA 02142, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA. Electronic address: [email protected].
⁷ Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA. Electronic address: [email protected].

Abstract

Cell differentiation and function are regulated across multiple layers of gene regulation, including modulation of gene expression by changes in chromatin accessibility. However, differentiation is an asynchronous process precluding a temporal understanding of regulatory events leading to cell fate commitment. Here we developed simultaneous high-throughput ATAC and RNA expression with sequencing (SHARE-seq), a highly scalable approach for measurement of chromatin accessibility and gene expression in the same single cell, applicable to different tissues. Using 34,774 joint profiles from mouse skin, we develop a computational strategy to identify cis-regulatory interactions and define domains of regulatory chromatin (DORCs) that significantly overlap with super-enhancers. During lineage commitment, chromatin accessibility at DORCs precedes gene expression, suggesting that changes in chromatin accessibility may prime cells for lineage commitment. We computationally infer chromatin potential as a quantitative measure of chromatin lineage-priming and use it to predict cell fate outcomes. SHARE-seq is an extensible platform to study regulatory circuitry across diverse cells in tissues.

Keywords: epigenomics; gene regulation; single cell; skin; stem cell.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Differentiation / genetics
Cell Line
Cell Lineage / genetics
Chromatin / metabolism*
Enhancer Elements, Genetic / genetics
Female
Gene Expression Profiling*
Gene Expression Regulation
Histones / metabolism
Mice, Inbred C57BL
Protein Processing, Post-Translational
RNA / genetics*
RNA / metabolism
Single-Cell Analysis*

Substances

Chromatin
Histones
RNA

Abstract

Publication types

MeSH terms

Substances

Grants and funding