Expansion in situ genome sequencing links nuclear abnormalities to aberrant chromatin regulation
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.
Authors
- Ruochi Zhang (ORCID: https://orcid.org/0000-0002-1103-5044)
- Ehsan Habibi (ORCID: https://orcid.org/0000-0002-7208-7999)
- Andrew Earl (ORCID: https://orcid.org/0000-0002-5732-954X)
- Zachary Chiang (ORCID: https://orcid.org/0000-0001-6578-2021)
- Rojesh Shrestha (ORCID: https://orcid.org/0000-0001-8742-5666)
- Ajay S. Labade (ORCID: https://orcid.org/0000-0003-1348-8220)
- Jason D. Buenrostro (ORCID: https://orcid.org/0000-0001-9958-3987)
- Fabiana M. Duarte (ORCID: https://orcid.org/0000-0002-1261-4929)
- George M. Church
- Caroline Comenho
- Paul Reginato (ORCID: https://orcid.org/0000-0002-7525-9047)
- Fei Chen (ORCID: https://orcid.org/0000-0003-2308-3649)
- Edward S. Boyden
- Andrew C. Payne
Institutions
- Broad Institute (US)
- Howard Hughes Medical Institute (US)
- Harvard University (US)
- McGovern Institute for Brain Research (US)
- IIT@MIT (US)
- The Centers (US)
- Massachusetts Institute of Technology (US)
Publication Details
- Journal
- Science
- Published
- 2025-05-29
- DOI
- https://doi.org/10.1126/science.adt2781
- Citations
- 6
- Primary Topic
- Genomics and Chromatin Dynamics
- Type
- article
- Field-Weighted Citation Impact
- 4.84