Integrative analysis of the 3D genome and epigenome in mouse embryonic tissues

Miao Yu; Nathan R Zemke; Ziyin Chen; Ivan Juric; Rong Hu; Ramya Raviram; Armen Abnousi; Rongxin Fang; Yanxiao Zhang; David U Gorkin; Yang E Li; Yuan Zhao; Lindsay Lee; Shreya Mishra; Anthony D Schmitt; Yunjiang Qiu; Diane E Dickel; Axel Visel; Len A Pennacchio; Ming Hu; Bing Ren

doi:10.1038/s41594-024-01431-2

Integrative analysis of the 3D genome and epigenome in mouse embryonic tissues

Nat Struct Mol Biol. 2024 Dec 16. doi: 10.1038/s41594-024-01431-2. Online ahead of print.

Authors

Miao Yu^#^{1

2}, Nathan R Zemke^#^{3

4}, Ziyin Chen^#⁵, Ivan Juric^{6

7}, Rong Hu⁸, Ramya Raviram^{8

9}, Armen Abnousi^{6

10}, Rongxin Fang^{11

12}, Yanxiao Zhang^{8

13}, David U Gorkin^{4

14}, Yang E Li^{8

15}, Yuan Zhao¹¹, Lindsay Lee⁶, Shreya Mishra⁶, Anthony D Schmitt^{8

16

17}, Yunjiang Qiu^{8

11

18}, Diane E Dickel¹⁹, Axel Visel^{19

20

21}, Len A Pennacchio^{19

20

22}, Ming Hu²³, Bing Ren^{24

25}

Affiliations

¹ State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, China. [email protected].
² Ludwig Institute for Cancer Research, La Jolla, CA, USA. [email protected].
³ Department of Cellular and Molecular Medicine, University of California, San Diego School of Medicine, La Jolla, CA, USA.
⁴ Center for Epigenomics, University of California, San Diego School of Medicine, La Jolla, CA, USA.
⁵ State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, China.
⁶ Department of Quantitative Health Sciences, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, USA.
⁷ Center for Immunology and Precision Immuno-Oncology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, USA.
⁸ Ludwig Institute for Cancer Research, La Jolla, CA, USA.
⁹ New York Genome Center, New York, NY, USA.
¹⁰ Meta, Bellevue, WA, USA.
¹¹ Bioinformatics and Systems Biology Graduate Program, University of California, San Diego, La Jolla, CA, USA.
¹² Howard Hughes Medical Institute, Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA, USA.
¹³ School of Life Sciences, Westlake University, Hangzhou, China.
¹⁴ Department of Biology, Emory University, Atlanta, GA, USA.
¹⁵ Department of Neurosurgery and Genetics, Washington University School of Medicine, St. Louis, MO, USA.
¹⁶ UCSD Biomedical Sciences Graduate Program, University of California, San Diego, La Jolla, CA, USA.
¹⁷ Arima Genomics, Inc., San Diego, CA, USA.
¹⁸ Sana Biotechnology, Seattle, WA, USA.
¹⁹ Environmental Genomics and Systems Biology Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA.
²⁰ US Department of Energy Joint Genome Institute, Berkeley, CA, USA.
²¹ School of Natural Sciences, University of California, Merced, Merced, CA, USA.
²² Comparative Biochemistry Program, University of California, Berkeley, Berkeley, CA, USA.
²³ Department of Quantitative Health Sciences, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, USA. [email protected].
²⁴ Department of Cellular and Molecular Medicine, University of California, San Diego School of Medicine, La Jolla, CA, USA. [email protected].
²⁵ Center for Epigenomics, University of California, San Diego School of Medicine, La Jolla, CA, USA. [email protected].

^# Contributed equally.

PMID: 39681766
DOI: 10.1038/s41594-024-01431-2

Abstract

While a rich set of putative cis-regulatory sequences involved in mouse fetal development have been annotated recently on the basis of chromatin accessibility and histone modification patterns, delineating their role in developmentally regulated gene expression continues to be challenging. To fill this gap, here we mapped chromatin contacts between gene promoters and distal sequences across the genome in seven mouse fetal tissues and across six developmental stages of the forebrain. We identified 248,620 long-range chromatin interactions centered at 14,138 protein-coding genes and characterized their tissue-to-tissue variations and developmental dynamics. Integrative analysis of the interactome with previous epigenome and transcriptome datasets from the same tissues revealed a strong correlation between the chromatin contacts and chromatin state at distal enhancers, as well as gene expression patterns at predicted target genes. We predicted target genes of 15,098 candidate enhancers and used them to annotate target genes of homologous candidate enhancers in the human genome that harbor risk variants of human diseases. We present evidence that schizophrenia and other adult disease risk variants are frequently found in fetal enhancers, providing support for the hypothesis of fetal origins of adult diseases.