In situ genome sequencing resolves DNA sequence and structure in intact biological samples

Andrew C. Payne; Zachary D. Chiang; Paul L. Reginato; Sarah M. Mangiameli; Evan M. Murray; Chun-Chen Yao; Styliani Markoulaki; Andrew S. Earl; Ajay S. Labade; Rudolf Jaenisch; George M. Church; Edward S. Boyden; Jason D. Buenrostro; Fei Chen

doi:10.1126/science.aay3446

Research Article

In situ genome sequencing resolves DNA sequence and structure in intact biological samples

View ORCID ProfileAndrew C. Payne ¹,²,*,
View ORCID ProfileZachary D. Chiang ²,³,*,
View ORCID ProfilePaul L. Reginato ¹,²,⁴,⁵,⁶,*,
View ORCID ProfileSarah M. Mangiameli²,
Evan M. Murray²,
Chun-Chen Yao²,⁷,
View ORCID ProfileStyliani Markoulaki⁸,
View ORCID ProfileAndrew S. Earl³,
View ORCID ProfileAjay S. Labade³,
View ORCID ProfileRudolf Jaenisch⁸,⁹,
View ORCID ProfileGeorge M. Church⁵,⁶,
View ORCID ProfileEdward S. Boyden¹,⁴,⁷,¹⁰,¹¹,¹²,¹³,†,
View ORCID ProfileJason D. Buenrostro ²,³,†,
View ORCID ProfileFei Chen ²,³,†

¹Media Arts and Sciences, Massachusetts Institute of Technology (MIT), Cambridge, MA 02139, USA.
²Broad Institute of MIT and Harvard University, Cambridge, MA 02142, USA.
³Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.
⁴Department of Biological Engineering, MIT, Cambridge, MA, 02139, USA.
⁵Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
⁶Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115, USA.
⁷Department of Brain and Cognitive Sciences, MIT, Cambridge, MA 02139, USA.
⁸Whitehead Institute for Biomedical Research, Cambridge, MA 02139, USA.
⁹Department of Biology, MIT, Cambridge, MA 02139, USA.
¹⁰McGovern Institute, MIT, Cambridge, MA 02139, USA.
¹¹Koch Institute, MIT, Cambridge, MA 02139, USA.
¹²Howard Hughes Medical Institute, Cambridge, MA 02139, USA.
¹³Centers for Neurobiological Engineering and Extreme Bionics, MIT, Cambridge, MA 02139, USA.

‡Corresponding author. Email: edboyden{at}mit.edu (E.S.B.); jason_buenrostro{at}harvard.edu (J.D.B.); chenf{at}broadinstitute.org (F.C.)

↵* These authors contributed equally to this work.
↵† These authors contributed equally to this work.

See allHide authors and affiliations

Science 31 Dec 2020:
eaay3446
DOI: 10.1126/science.aay3446

Andrew C. Payne

1Media Arts and Sciences, Massachusetts Institute of Technology (MIT), Cambridge, MA 02139, USA.

2Broad Institute of MIT and Harvard University, Cambridge, MA 02142, USA.

Find this author on Google Scholar
Find this author on PubMed
Search for this author on this site
ORCID record for Andrew C. Payne

Zachary D. Chiang

2Broad Institute of MIT and Harvard University, Cambridge, MA 02142, USA.

3Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.

Find this author on Google Scholar
Find this author on PubMed
Search for this author on this site
ORCID record for Zachary D. Chiang

Paul L. Reginato

1Media Arts and Sciences, Massachusetts Institute of Technology (MIT), Cambridge, MA 02139, USA.

2Broad Institute of MIT and Harvard University, Cambridge, MA 02142, USA.

4Department of Biological Engineering, MIT, Cambridge, MA, 02139, USA.

5Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.

6Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115, USA.

Find this author on Google Scholar
Find this author on PubMed
Search for this author on this site
ORCID record for Paul L. Reginato

Sarah M. Mangiameli

2Broad Institute of MIT and Harvard University, Cambridge, MA 02142, USA.

Find this author on Google Scholar
Find this author on PubMed
Search for this author on this site
ORCID record for Sarah M. Mangiameli

Evan M. Murray

2Broad Institute of MIT and Harvard University, Cambridge, MA 02142, USA.

Find this author on Google Scholar
Find this author on PubMed
Search for this author on this site

Chun-Chen Yao

2Broad Institute of MIT and Harvard University, Cambridge, MA 02142, USA.

7Department of Brain and Cognitive Sciences, MIT, Cambridge, MA 02139, USA.

Find this author on Google Scholar
Find this author on PubMed
Search for this author on this site

Styliani Markoulaki

8Whitehead Institute for Biomedical Research, Cambridge, MA 02139, USA.

Find this author on Google Scholar
Find this author on PubMed
Search for this author on this site
ORCID record for Styliani Markoulaki

Andrew S. Earl

3Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.

Find this author on Google Scholar
Find this author on PubMed
Search for this author on this site
ORCID record for Andrew S. Earl

Ajay S. Labade

3Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.

Find this author on Google Scholar
Find this author on PubMed
Search for this author on this site
ORCID record for Ajay S. Labade

Rudolf Jaenisch

8Whitehead Institute for Biomedical Research, Cambridge, MA 02139, USA.

9Department of Biology, MIT, Cambridge, MA 02139, USA.

Find this author on Google Scholar
Find this author on PubMed
Search for this author on this site
ORCID record for Rudolf Jaenisch

George M. Church

5Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.

6Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115, USA.

Find this author on Google Scholar
Find this author on PubMed
Search for this author on this site
ORCID record for George M. Church

Edward S. Boyden

1Media Arts and Sciences, Massachusetts Institute of Technology (MIT), Cambridge, MA 02139, USA.

4Department of Biological Engineering, MIT, Cambridge, MA, 02139, USA.

7Department of Brain and Cognitive Sciences, MIT, Cambridge, MA 02139, USA.

10McGovern Institute, MIT, Cambridge, MA 02139, USA.

11Koch Institute, MIT, Cambridge, MA 02139, USA.

12Howard Hughes Medical Institute, Cambridge, MA 02139, USA.

13Centers for Neurobiological Engineering and Extreme Bionics, MIT, Cambridge, MA 02139, USA.

Find this author on Google Scholar
Find this author on PubMed
Search for this author on this site
ORCID record for Edward S. Boyden

Jason D. Buenrostro

2Broad Institute of MIT and Harvard University, Cambridge, MA 02142, USA.

3Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.

Find this author on Google Scholar
Find this author on PubMed
Search for this author on this site
ORCID record for Jason D. Buenrostro

Fei Chen

2Broad Institute of MIT and Harvard University, Cambridge, MA 02142, USA.

3Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.

Find this author on Google Scholar
Find this author on PubMed
Search for this author on this site
ORCID record for Fei Chen

Article
Figures & Data
Info & Metrics
eLetters
PDF

You are currently viewing the abstract.

View Full Text

Log in to view the full text

via AAAS login

AAAS login provides access to Science for AAAS members, and access to other journals in the Science family to users who have purchased individual subscriptions.

Become an AAAS Member
Activate your Account
Purchase Access to Other Journals in the Science Family
Account Help

Log in through your institution

More options

Purchase digital access to this article

Download and print this article for your personal scholarly, research, and educational use.

Purchase this issue in print

Buy a single issue of Science for just $15 USD.

Abstract

Understanding genome organization requires integration of DNA sequence and 3D spatial context, however, existing genome-wide methods lack either base-pair sequence resolution or direct spatial localization. Here, we describe in situ genome sequencing (IGS), a method for simultaneously sequencing and imaging genomes within intact biological samples. We applied IGS to human fibroblasts and early mouse embryos, spatially localizing thousands of genomic loci in individual nuclei. Using these data, we characterized parent-specific changes in genome structure across embryonic stages, revealed single-cell chromatin domains in zygotes, and uncovered epigenetic memory of global chromosome positioning within individual embryos. These results demonstrate how in situ genome sequencing can directly connect sequence and structure across length scales from single base pairs to whole organisms.

View Full Text

In situ genome sequencing resolves DNA sequence and structure in intact biological samples

Abstract

Article Tools