Expansion in situ genome sequencing links nuclear abnormalities to aberrant chromatin regulation

Ajay S Labade^#^{1

2

3}, Zachary D Chiang^#^{1

2

3}, Caroline Comenho^#^{1

2

3}, Paul L Reginato^{3

4

5

6

7}, Andrew C Payne^{3

6}, Andrew S Earl^{1

2

3}, Rojesh Shrestha^{1

2

3}, Fabiana M Duarte^{1

2

3}, Ehsan Habibi³, Ruochi Zhang^{1

2

3}, George M Church^{4

5}, Edward S Boyden^{6

7

8

9

10

11

12}, Fei Chen^{1

2

3}, Jason D Buenrostro^{1

2

3}

Affiliations

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

^# Contributed equally.

PMID: 40440430
DOI: 10.1126/science.adt2781

Expansion in situ genome sequencing links nuclear abnormalities to aberrant chromatin regulation

Ajay S Labade et al. Science. 2025.

. 2025 Jul 24;389(6758):eadt2781.

doi: 10.1126/science.adt2781. Epub 2025 Jul 24.

Authors

Affiliations

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

^# Contributed equally.

PMID: 40440430
DOI: 10.1126/science.adt2781

Abstract

Microscopy and genomics are used to characterize cell function, but approaches to connect the two types of information are lacking, particularly at subnuclear resolution. Here, we describe expansion in situ genome sequencing (ExIGS), a technology that enables sequencing of genomic DNA and super-resolution localization of nuclear proteins in single cells. Applying ExIGS to progeria-derived fibroblasts revealed that lamin abnormalities are linked to hotspots of aberrant chromatin regulation that may erode cell identity. Lamin was found to generally repress transcription, suggesting that variation in nuclear morphology may affect gene regulation across tissues and aged cells. These results demonstrate that ExIGS may serve as a generalizable platform with which to link nuclear abnormalities to gene regulation, offering insights into disease mechanisms.

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Update of

Expansion in situ genome sequencing links nuclear abnormalities to hotspots of aberrant euchromatin repression.
Labade AS, Chiang ZD, Comenho C, Reginato PL, Payne AC, Earl AS, Shrestha R, Duarte FM, Habibi E, Zhang R, Church GM, Boyden ES, Chen F, Buenrostro JD. Labade AS, et al. bioRxiv [Preprint]. 2024 Sep 26:2024.09.24.614614. doi: 10.1101/2024.09.24.614614. bioRxiv. 2024. Update in: Science. 2025 Jul 24;389(6758):eadt2781. doi: 10.1126/science.adt2781. PMID: 39386718 Free PMC article. Updated. Preprint.

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Expansion in situ genome sequencing links nuclear abnormalities to aberrant chromatin regulation

Affiliations

Expansion in situ genome sequencing links nuclear abnormalities to aberrant chromatin regulation

Authors

Affiliations

Abstract

Update of

MeSH terms

Substances

LinkOut - more resources

Full Text Sources