3D genomics across the tree of life reveals condensin II as a determinant of architecture type

doi:10.1126/science.abe2218

. 2021 May 28;372(6545):984-989.

doi: 10.1126/science.abe2218.

3D genomics across the tree of life reveals condensin II as a determinant of architecture type

Claire Hoencamp^#¹, Olga Dudchenko^#^{2

3

4}, Ahmed M O Elbatsh^#¹, Sumitabha Brahmachari^#⁴, Jonne A Raaijmakers^#⁵, Tom van Schaik^#⁶, Ángela Sedeño Cacciatore^#¹, Vinícius G Contessoto^#^{4

7}, Roy G H P van Heesbeen^#⁵, Bram van den Broek⁸, Aditya N Mhaskar¹, Hans Teunissen⁶, Brian Glenn St Hilaire^{2

3}, David Weisz^{2

3}, Arina D Omer², Melanie Pham², Zane Colaric², Zhenzhen Yang⁹, Suhas S P Rao^{2

3

10}, Namita Mitra^{2

3}, Christopher Lui², Weijie Yao², Ruqayya Khan^{2

3}, Leonid L Moroz¹¹, Andrea Kohn¹¹, Judy St Leger¹², Alexandria Mena¹³, Karen Holcroft¹⁴, Maria Cristina Gambetta¹⁵, Fabian Lim¹⁶, Emma Farley¹⁶, Nils Stein^{17

18

19}, Alexander Haddad², Daniel Chauss²⁰, Ayse Sena Mutlu³, Meng C Wang^{3

21

22}, Neil D Young²³, Evin Hildebrandt²⁴, Hans H Cheng²⁴, Christopher J Knight²⁵, Theresa L U Burnham^{26

27}, Kevin A Hovel²⁷, Andrew J Beel¹⁰, Pierre-Jean Mattei¹⁰, Roger D Kornberg¹⁰, Wesley C Warren²⁸, Gregory Cary²⁹, José Luis Gómez-Skarmeta³⁰, Veronica Hinman³¹, Kerstin Lindblad-Toh^{32

33}, Federica Di Palma³⁴, Kazuhiro Maeshima^{35

36}, Asha S Multani³⁷, Sen Pathak³⁷, Liesl Nel-Themaat³⁷, Richard R Behringer³⁷, Parwinder Kaur¹⁹, René H Medema⁵, Bas van Steensel⁶, Elzo de Wit⁶, José N Onuchic^{4

38}, Michele Di Pierro^{4

39}, Erez Lieberman Aiden^{40

3

4

9

19

32}, Benjamin D Rowland⁴¹

Affiliations

¹ Division of Gene Regulation, Netherlands Cancer Institute, 1066 CX Amsterdam, Netherlands.
² The Center for Genome Architecture, Baylor College of Medicine, Houston, TX 77030, USA.
³ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
⁴ Center for Theoretical Biological Physics, Rice University, Houston, TX 77005, USA.
⁵ Division of Cell Biology, Oncode Institute, Netherlands Cancer Institute, 1066 CX Amsterdam, Netherlands.
⁶ Division of Gene Regulation, Oncode Institute, Netherlands Cancer Institute, 1066 CX Amsterdam, Netherlands.
⁷ Department of Physics, Institute of Biosciences, Letters and Exact Sciences, São Paulo State University (UNESP), São José do Rio Preto - SP, 15054-000, Brazil.
⁸ BioImaging Facility, Netherlands Cancer Institute, 1066 CX Amsterdam, Netherlands.
⁹ Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech, Pudong 201210, China.
¹⁰ Department of Structural Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
¹¹ Whitney Laboratory and Department of Neuroscience, University of Florida, Gainesville, FL 32611, USA.
¹² Department of Biosciences, Cornell University College of Veterinary Medicine, Ithaca, NY 14853, USA.
¹³ SeaWorld San Diego, San Diego, CA 92109, USA.
¹⁴ Moody Gardens, Galveston, TX 77554, USA.
¹⁵ Center for Integrative Genomics, University of Lausanne, 1015 Lausanne, Switzerland.
¹⁶ Department of Medicine and Molecular Biology, University of California, San Diego, La Jolla, CA 92093, USA.
¹⁷ Leibniz Institute of Plant Genetics and Crop Plant Research (IPK Gatersleben), 06466 Seeland, Germany.
¹⁸ Center of Integrated Breeding Research (CiBreed), Department of Crop Sciences, Georg-August-University Göttingen, 37075 Göttingen, Germany.
¹⁹ UWA School of Agriculture and Environment, The University of Western Australia, Perth, WA 6009, Australia.
²⁰ National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
²¹ Huffington Center on Aging, Baylor College of Medicine, Houston, TX 77030, USA.
²² Howard Hughes Medical Institute, Baylor College of Medicine, Houston, TX 77030, USA.
²³ Faculty of Veterinary and Agricultural Sciences, University of Melbourne, Parkville, VIC 3010, Australia.
²⁴ Avian Diseases and Oncology Laboratory, US Department of Agriculture, Agricultural Research Service, East Lansing, MI 48823, USA.
²⁵ Hopkins Marine Station, Stanford University, Pacific Grove, CA 93950, USA.
²⁶ Department of Wildlife, Fish, and Conservation Biology, University of California, Davis, Davis, CA 95616, USA.
²⁷ Coastal and Marine Institute and Department of Biology, San Diego State University, San Diego, CA 92106, USA.
²⁸ Department of Animal Sciences, University of Missouri, Columbia, MO 65211, USA.
²⁹ The Jackson Laboratory, Bar Harbor, ME 04609, USA.
³⁰ Centro Andaluz de Biología del Desarrollo CSIC, Universidad Pablo de Olavide, 41013 Sevilla, Spain.
³¹ Department of Biological Sciences, Carnegie Mellon University, Pittsburgh, PA 15213, USA.
³² Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
³³ Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, 751 23 Uppsala, Sweden.
³⁴ Department of Biological Sciences, University of East Anglia, Norwich NR4 7TJ, UK.
³⁵ Genome Dynamics Laboratory, National Institute of Genetics, Mishima, Shizuoka 411-8540, Japan.
³⁶ Department of Genetics, Sokendai (Graduate University for Advanced Studies), Mishima, Shizuoka 411-8540, Japan.
³⁷ Department of Genetics, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
³⁸ Departments of Physics and Astronomy, Chemistry, and Biosciences, Rice University, Houston, TX 77005, USA.
³⁹ Department of Physics, Northeastern University, Boston, MA 02115, USA.
⁴⁰ The Center for Genome Architecture, Baylor College of Medicine, Houston, TX 77030, USA. b.rowland@nki.nl erez@erez.com.
⁴¹ Division of Gene Regulation, Netherlands Cancer Institute, 1066 CX Amsterdam, Netherlands. b.rowland@nki.nl erez@erez.com.

^# Contributed equally.

PMID: 34045355
PMCID: PMC8172041
DOI: 10.1126/science.abe2218

3D genomics across the tree of life reveals condensin II as a determinant of architecture type

Claire Hoencamp et al. Science. 2021.

. 2021 May 28;372(6545):984-989.

doi: 10.1126/science.abe2218.

Authors

Affiliations

¹ Division of Gene Regulation, Netherlands Cancer Institute, 1066 CX Amsterdam, Netherlands.
² The Center for Genome Architecture, Baylor College of Medicine, Houston, TX 77030, USA.
³ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
⁴ Center for Theoretical Biological Physics, Rice University, Houston, TX 77005, USA.
⁵ Division of Cell Biology, Oncode Institute, Netherlands Cancer Institute, 1066 CX Amsterdam, Netherlands.
⁶ Division of Gene Regulation, Oncode Institute, Netherlands Cancer Institute, 1066 CX Amsterdam, Netherlands.
⁷ Department of Physics, Institute of Biosciences, Letters and Exact Sciences, São Paulo State University (UNESP), São José do Rio Preto - SP, 15054-000, Brazil.
⁸ BioImaging Facility, Netherlands Cancer Institute, 1066 CX Amsterdam, Netherlands.
⁹ Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech, Pudong 201210, China.
¹⁰ Department of Structural Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
¹¹ Whitney Laboratory and Department of Neuroscience, University of Florida, Gainesville, FL 32611, USA.
¹² Department of Biosciences, Cornell University College of Veterinary Medicine, Ithaca, NY 14853, USA.
¹³ SeaWorld San Diego, San Diego, CA 92109, USA.
¹⁴ Moody Gardens, Galveston, TX 77554, USA.
¹⁵ Center for Integrative Genomics, University of Lausanne, 1015 Lausanne, Switzerland.
¹⁶ Department of Medicine and Molecular Biology, University of California, San Diego, La Jolla, CA 92093, USA.
¹⁷ Leibniz Institute of Plant Genetics and Crop Plant Research (IPK Gatersleben), 06466 Seeland, Germany.
¹⁸ Center of Integrated Breeding Research (CiBreed), Department of Crop Sciences, Georg-August-University Göttingen, 37075 Göttingen, Germany.
¹⁹ UWA School of Agriculture and Environment, The University of Western Australia, Perth, WA 6009, Australia.
²⁰ National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
²¹ Huffington Center on Aging, Baylor College of Medicine, Houston, TX 77030, USA.
²² Howard Hughes Medical Institute, Baylor College of Medicine, Houston, TX 77030, USA.
²³ Faculty of Veterinary and Agricultural Sciences, University of Melbourne, Parkville, VIC 3010, Australia.
²⁴ Avian Diseases and Oncology Laboratory, US Department of Agriculture, Agricultural Research Service, East Lansing, MI 48823, USA.
²⁵ Hopkins Marine Station, Stanford University, Pacific Grove, CA 93950, USA.
²⁶ Department of Wildlife, Fish, and Conservation Biology, University of California, Davis, Davis, CA 95616, USA.
²⁷ Coastal and Marine Institute and Department of Biology, San Diego State University, San Diego, CA 92106, USA.
²⁸ Department of Animal Sciences, University of Missouri, Columbia, MO 65211, USA.
²⁹ The Jackson Laboratory, Bar Harbor, ME 04609, USA.
³⁰ Centro Andaluz de Biología del Desarrollo CSIC, Universidad Pablo de Olavide, 41013 Sevilla, Spain.
³¹ Department of Biological Sciences, Carnegie Mellon University, Pittsburgh, PA 15213, USA.
³² Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
³³ Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, 751 23 Uppsala, Sweden.
³⁴ Department of Biological Sciences, University of East Anglia, Norwich NR4 7TJ, UK.
³⁵ Genome Dynamics Laboratory, National Institute of Genetics, Mishima, Shizuoka 411-8540, Japan.
³⁶ Department of Genetics, Sokendai (Graduate University for Advanced Studies), Mishima, Shizuoka 411-8540, Japan.
³⁷ Department of Genetics, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
³⁸ Departments of Physics and Astronomy, Chemistry, and Biosciences, Rice University, Houston, TX 77005, USA.
³⁹ Department of Physics, Northeastern University, Boston, MA 02115, USA.
⁴⁰ The Center for Genome Architecture, Baylor College of Medicine, Houston, TX 77030, USA. b.rowland@nki.nl erez@erez.com.
⁴¹ Division of Gene Regulation, Netherlands Cancer Institute, 1066 CX Amsterdam, Netherlands. b.rowland@nki.nl erez@erez.com.

^# Contributed equally.

PMID: 34045355
PMCID: PMC8172041
DOI: 10.1126/science.abe2218

Abstract

We investigated genome folding across the eukaryotic tree of life. We find two types of three-dimensional (3D) genome architectures at the chromosome scale. Each type appears and disappears repeatedly during eukaryotic evolution. The type of genome architecture that an organism exhibits correlates with the absence of condensin II subunits. Moreover, condensin II depletion converts the architecture of the human genome to a state resembling that seen in organisms such as fungi or mosquitoes. In this state, centromeres cluster together at nucleoli, and heterochromatin domains merge. We propose a physical model in which lengthwise compaction of chromosomes by condensin II during mitosis determines chromosome-scale genome architecture, with effects that are retained during the subsequent interphase. This mechanism likely has been conserved since the last common ancestor of all eukaryotes.

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Conflict of interest statement

Competing interests

All authors declare that they have no competing interests.

Figures

**Figure 1.. A comprehensive overview of genome organization across evolution**
Aggregate chromosome analysis (ACA) on Hi-C maps of 24 species. ACA involves the scaling of chromosome arms to a uniform length and aggregating the signal of all intra- and inter-chromosomal contacts. The depicted species represent three kingdoms: animals (yellow), fungi (blue) and plants (green), whose evolutionary relationship is presented in the phylogenetic tree. Each corner shows an example ACA map and a schematic drawing of one of the four chromosome-scale features. Presence of the condensin II subunits in each species is indicated by solid black circles. Left to right: SMC2/SMC4/CAP-H2/CAP-G2/CAP-D3.

**Figure 2.. Condensin II prevents centromeric clustering and keeps apart heterochromatin domains**
(a) Hi-C matrices of the depicted genotypes in Hap1 cells. (b) Immunofluorescence of centromeres (CREST) and DNA (DAPI), as quantified in (c). (d) Difference in DamID score relative to distance to centromere. Zoom-in includes 95% confidence interval of the mean in grey. (e) Immunofluorescence of centromeres (CREST), nucleoli (Nucleolin) and DNA (DAPI) (f) Quantification of the fraction of centromere intensity within 0.4 μm of nucleoli as shown in (e). (g) Immunofluorescence of centromeres (CenpA), heterochromatin (H3K9me3) and DNA (DAPI), as quantified in (h).

**Figure 3.. Massive 3D genome changes hardly affect gene expression**
(a) Gene expression of wild type relative to Δ*CAP-H2*. Unaffected genes depicted in grey, upregulated genes in blue and downregulated in red. (b) Number of genes in each category. (c) Percentage of active genes overlapping with LADs. (d) Intersection of differences in gene expression with differences in lamina association, depicting active genes within LADs. (e) Schematic model of centromeres (red) moving to the inner nucleus, and silenced genes that now localize to the lamina.

**Figure 4.. Centromeric clustering is counteracted by lengthwise compaction and requires mitosis-to-interphase transition**
(a) Quantification of centromeric foci before or after mitotic progression with/without condensin II. FACS plots depict cell cycle stages. Outliers (>60) were truncated and depicted as squares. (b) Example images of G1 cells as quantified in (a). (c-g) Simulation modeling using ten polymer chains as chromosomes. (c) Number of centromere clusters upon varying lengthwise compaction. ‘WT’ and ‘ΔC’ correspond to higher and lower lengthwise compaction, best recapitulating the experimental data observed in wild type and Δ*CAP-H2* cells. Top: representative models for both states. (d) Representative simulation snapshots depicting ten chromosomes in different colors. (e) Quantification of the ratio of cis-contacts. (f) Simulated Hi-C matrices depicting contacts between the respective chromosomes. (g) Quantification of the proportion of trans-centromeric contacts.

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[1] Rao SSP et al., Cell. 159, 1665–1680 (2014). - PMC - PubMed

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[10] Hirano T, Cell. 164, 847–857 (2016). - PubMed

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3D genomics across the tree of life reveals condensin II as a determinant of architecture type

Affiliations

3D genomics across the tree of life reveals condensin II as a determinant of architecture type

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