Single-cell multi-scale footprinting reveals the modular organization of DNA regulatory elements.

Autor:	Hu Y; Gene Regulation Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, 02142 USA.; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, 02138 USA., Ma S; Gene Regulation Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, 02142 USA.; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, 02138 USA.; Current address: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029 USA., Kartha VK; Gene Regulation Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, 02142 USA.; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, 02138 USA., Duarte FM; Gene Regulation Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, 02142 USA.; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, 02138 USA., Horlbeck M; Gene Regulation Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, 02142 USA.; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, 02138 USA., Zhang R; Gene Regulation Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, 02142 USA.; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, 02138 USA., Shrestha R; Gene Regulation Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, 02142 USA.; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, 02138 USA., Labade A; Gene Regulation Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, 02142 USA.; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, 02138 USA., Kletzien H; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, 02138 USA.; Paul F. Glenn Center for the Biology of Aging, Harvard Medical School, Boston, MA 02115., Meliki A; Gene Regulation Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, 02142 USA.; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, 02138 USA., Castillo A; Gene Regulation Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, 02142 USA.; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, 02138 USA., Durand N; Gene Regulation Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, 02142 USA., Mattei E; Gene Regulation Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, 02142 USA., Anderson LJ; Gene Regulation Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, 02142 USA., Tay T; Gene Regulation Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, 02142 USA.; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, 02138 USA., Earl AS; Gene Regulation Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, 02142 USA.; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, 02138 USA., Shoresh N; Gene Regulation Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, 02142 USA., Epstein CB; Gene Regulation Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, 02142 USA., Wagers A; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, 02138 USA.; Paul F. Glenn Center for the Biology of Aging, Harvard Medical School, Boston, MA 02115., Buenrostro JD; Gene Regulation Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, 02142 USA.; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, 02138 USA.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2023 Mar 29. Date of Electronic Publication: 2023 Mar 29.
DOI:	10.1101/2023.03.28.533945
Abstrakt:	Cis -regulatory elements control gene expression and are dynamic in their structure, reflecting changes to the composition of diverse effector proteins over time 1-3 . Here we sought to connect the structural changes at cis- regulatory elements to alterations in cellular fate and function. To do this we developed PRINT, a computational method that uses deep learning to correct sequence bias in chromatin accessibility data and identifies multi-scale footprints of DNA-protein interactions. We find that multi-scale footprints enable more accurate inference of TF and nucleosome binding. Using PRINT with single-cell multi-omics, we discover wide-spread changes to the structure and function of candidate cis -regulatory elements (cCREs) across hematopoiesis, wherein nucleosomes slide, expose DNA for TF binding, and promote gene expression. Activity segmentation using the co-variance across cell states identifies "sub-cCREs" as modular cCRE subunits of regulatory DNA. We apply this single-cell and PRINT approach to characterize the age-associated alterations to cCREs within hematopoietic stem cells (HSCs). Remarkably, we find a spectrum of aging alterations among HSCs corresponding to a global gain of sub-cCRE activity while preserving cCRE accessibility. Collectively, we reveal the functional importance of cCRE structure across cell states, highlighting changes to gene regulation at single-cell and single-base-pair resolution. Competing Interests: Declaration of Interests J. Buenrostro holds patents related to ATAC-seq and is an SAB member of Camp4 and seqWell. J. Buenrostro and S. Ma holds a patent based on SHARE-seq. A.J.W. is a scientific advisor for Frequency Therapeutics and Kate Therapeutics. A.J.W. is also a co-founder and scientific advisory board member and holds private equity in Elevian, Inc., a company that aims to develop medicines to restore regenerative capacity. Elevian also provides sponsored research to the Wagers lab.
Databáze:	MEDLINE
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