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Published July 26, 2018 | Supplemental Material + Accepted Version + Submitted
Journal Article Open

Higher-Order Inter-chromosomal Hubs Shape 3D Genome Organization in the Nucleus

Abstract

Eukaryotic genomes are packaged into a 3-dimensional structure in the nucleus. Current methods for studying genome-wide structure are based on proximity ligation. However, this approach can fail to detect known structures, such as interactions with nuclear bodies, because these DNA regions can be too far apart to directly ligate. Accordingly, our overall understanding of genome organization remains incomplete. Here, we develop split-pool recognition of interactions by tag extension (SPRITE), a method that enables genome-wide detection of higher-order interactions within the nucleus. Using SPRITE, we recapitulate known structures identified by proximity ligation and identify additional interactions occurring across larger distances, including two hubs of inter-chromosomal interactions that are arranged around the nucleolus and nuclear speckles. We show that a substantial fraction of the genome exhibits preferential organization relative to these nuclear bodies. Our results generate a global model whereby nuclear bodies act as inter-chromosomal hubs that shape the overall packaging of DNA in the nucleus.

Additional Information

© 2018 Elsevier Inc. Received 14 November 2017, Revised 18 March 2018, Accepted 10 May 2018, Available online 7 June 2018, Published: June 7, 2018. We thank F. Alber, J. Jachowicz, A. Lin, K. Plath, J. Rinn, M. Thomson, W.G. Walkup, and B. Wold for manuscript comments; S. Knemeyer for illustrations; and B. Belin for naming SPRITE. Imaging was performed in the Biological Imaging Facility, with advice from A. Collazo and S. Wilbert. Sequencing was performed at the Millard and Muriel Jacobs Genetics and Genomics Laboratory with assistance from I. Antoshechkin. S.A.Q. was funded by a HHMI Gilliam Fellowship and NSF GRFP Fellowship. P.B. was funded by NIGMS (T32 GM008042) and UCLA-Caltech MSTP (NIGMS T32 GM008042). This work was funded by the NIH 4DN Program (U01 DA040612 and U01 HL130007), NHGRI GGR Program (U01 HG007910), New York Stem Cell Foundation (NYSCF-R-I13), Sontag Foundation, and funds from Caltech. M. Guttman is a NYSCF-Robertson Investigator. Author Contributions: Conceptualization, S.A.Q., C.C., M.J., and M. Guttman; Methodology, S.A.Q., N.O., B.T., J.M.S., A.A.S., A.C., Y.T., P.M., M. Garber, and M. Guttman; Software, N.O., B.T., M.M.L., P.R., and M. Guttman; Validation, S.A.Q., A.P., and Y.T.; Formal Analysis, S.A.Q., N.O., B.T., A.P., M.L., M. Garber, and M. Guttman; Investigation, S.A.Q., A.P., J.M.S., E.D., A.A.S., P.B., V.T., E.A., A.C., and Y.T.; Resources, L.C., M. Garber, and M. Guttman; Data Curation, S.A.Q., N.O., M.L., B.T., and M. Guttman; Writing, S.A.Q., N.O., and M. Guttman; Supervision, S.A.Q., M. Garber, and M. Guttman; and Funding Acquisition, M. Guttman. Declaration of Interests: S.A.Q. and M.G. are inventors on a provisional patent on the SPRITE method.

Attached Files

Accepted Version - nihms972930.pdf

Submitted - 219683.full.pdf

Supplemental Material - mmc1.xlsx

Supplemental Material - mmc2.xlsx

Supplemental Material - mmc3.xlsx

Supplemental Material - mmc4.xlsx

Supplemental Material - mmc5.xlsx

Supplemental Material - mmc6.xlsx

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Additional details

Created:
August 21, 2023
Modified:
October 23, 2023