Landscape of X chromosome inactivation across human tissues
X chromosome inactivation (XCI) silences transcription from one of the two X chromosomes in female mammalian cells to balance expression dosage between XX females and XY males. XCI is, however, incomplete in humans: up to one-third of X-chromosomal genes are expressed from both the active and inacti...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Other Authors: | |
| Format: | Article |
| Published: |
Springer Nature
2018
|
| Online Access: | http://hdl.handle.net/1721.1/116808 https://orcid.org/0000-0001-5951-9358 https://orcid.org/0000-0001-8567-2049 |
| _version_ | 1811086480829841408 |
|---|---|
| author | Tukiainen, Taru Villani, Alexandra-Chloé Rivas, Manuel A. Marshall, Jamie L. Satija, Rahul Aguirre, Matt Gauthier, Laura Fleharty, Mark Kirby, Andrew Cummings, Beryl B. Castel, Stephane E. Karczewski, Konrad J. Aguet, François Byrnes, Andrea Aguet, François Ardlie, Kristin G. Cummings, Beryl B. Gelfand, Ellen T. Getz, Gad Hadley, Kane Handsaker, Robert E. Huang, Katherine H. Kashin, Seva Karczewski, Konrad J. Lek, Monkol Li, Xiao MacArthur, Daniel G. Yen, Angela Regev, Aviv |
| author2 | Massachusetts Institute of Technology. Computer Science and Artificial Intelligence Laboratory |
| author_facet | Massachusetts Institute of Technology. Computer Science and Artificial Intelligence Laboratory Tukiainen, Taru Villani, Alexandra-Chloé Rivas, Manuel A. Marshall, Jamie L. Satija, Rahul Aguirre, Matt Gauthier, Laura Fleharty, Mark Kirby, Andrew Cummings, Beryl B. Castel, Stephane E. Karczewski, Konrad J. Aguet, François Byrnes, Andrea Aguet, François Ardlie, Kristin G. Cummings, Beryl B. Gelfand, Ellen T. Getz, Gad Hadley, Kane Handsaker, Robert E. Huang, Katherine H. Kashin, Seva Karczewski, Konrad J. Lek, Monkol Li, Xiao MacArthur, Daniel G. Yen, Angela Regev, Aviv |
| author_sort | Tukiainen, Taru |
| collection | MIT |
| description | X chromosome inactivation (XCI) silences transcription from one of the two X chromosomes in female mammalian cells to balance expression dosage between XX females and XY males. XCI is, however, incomplete in humans: up to one-third of X-chromosomal genes are expressed from both the active and inactive X chromosomes (Xa and Xi, respectively) in female cells, with the degree of 'escape' from inactivation varying between genes and individuals1,2. The extent to which XCI is shared between cells and tissues remains poorly characterized3,4, as does the degree to which incomplete XCI manifests as detectable sex differences in gene expression5 and phenotypic traits6. Here we describe a systematic survey of XCI, integrating over 5,500 transcriptomes from 449 individuals spanning 29 tissues from GTEx (v6p release) and 940 single-cell transcriptomes, combined with genomic sequence data. We show that XCI at 683 X-chromosomal genes is generally uniform across human tissues, but identify examples of heterogeneity between tissues, individuals and cells. We show that incomplete XCI affects at least 23% of X-chromosomal genes, identify seven genes that escape XCI with support from multiple lines of evidence and demonstrate that escape from XCI results in sex biases in gene expression, establishing incomplete XCI as a mechanism that is likely to introduce phenotypic diversity6,7. Overall, this updated catalogue of XCI across human tissues helps to increase our understanding of the extent and impact of the incompleteness in the maintenance of XCI. |
| first_indexed | 2024-09-23T13:26:36Z |
| format | Article |
| id | mit-1721.1/116808 |
| institution | Massachusetts Institute of Technology |
| last_indexed | 2024-09-23T13:26:36Z |
| publishDate | 2018 |
| publisher | Springer Nature |
| record_format | dspace |
| spelling | mit-1721.1/1168082022-09-28T14:19:27Z Landscape of X chromosome inactivation across human tissues Tukiainen, Taru Villani, Alexandra-Chloé Rivas, Manuel A. Marshall, Jamie L. Satija, Rahul Aguirre, Matt Gauthier, Laura Fleharty, Mark Kirby, Andrew Cummings, Beryl B. Castel, Stephane E. Karczewski, Konrad J. Aguet, François Byrnes, Andrea Aguet, François Ardlie, Kristin G. Cummings, Beryl B. Gelfand, Ellen T. Getz, Gad Hadley, Kane Handsaker, Robert E. Huang, Katherine H. Kashin, Seva Karczewski, Konrad J. Lek, Monkol Li, Xiao MacArthur, Daniel G. Yen, Angela Regev, Aviv Massachusetts Institute of Technology. Computer Science and Artificial Intelligence Laboratory Massachusetts Institute of Technology. Department of Biology Massachusetts Institute of Technology. Department of Electrical Engineering and Computer Science Yen, Angela Regev, Aviv X chromosome inactivation (XCI) silences transcription from one of the two X chromosomes in female mammalian cells to balance expression dosage between XX females and XY males. XCI is, however, incomplete in humans: up to one-third of X-chromosomal genes are expressed from both the active and inactive X chromosomes (Xa and Xi, respectively) in female cells, with the degree of 'escape' from inactivation varying between genes and individuals1,2. The extent to which XCI is shared between cells and tissues remains poorly characterized3,4, as does the degree to which incomplete XCI manifests as detectable sex differences in gene expression5 and phenotypic traits6. Here we describe a systematic survey of XCI, integrating over 5,500 transcriptomes from 449 individuals spanning 29 tissues from GTEx (v6p release) and 940 single-cell transcriptomes, combined with genomic sequence data. We show that XCI at 683 X-chromosomal genes is generally uniform across human tissues, but identify examples of heterogeneity between tissues, individuals and cells. We show that incomplete XCI affects at least 23% of X-chromosomal genes, identify seven genes that escape XCI with support from multiple lines of evidence and demonstrate that escape from XCI results in sex biases in gene expression, establishing incomplete XCI as a mechanism that is likely to introduce phenotypic diversity6,7. Overall, this updated catalogue of XCI across human tissues helps to increase our understanding of the extent and impact of the incompleteness in the maintenance of XCI. 2018-07-05T19:28:22Z 2018-07-05T19:28:22Z 2017-10 2016-08 2018-07-02T19:13:29Z Article http://purl.org/eprint/type/JournalArticle 0028-0836 1476-4687 http://hdl.handle.net/1721.1/116808 Tukiainen, Taru, Alexandra-Chloé Villani, Angela Yen, Manuel A. Rivas, Jamie L. Marshall, Rahul Satija, Matt Aguirre, et al. “Landscape of X Chromosome Inactivation Across Human Tissues.” Nature 550, no. 7675 (October 11, 2017): 244–248 © 2017 Macmillan Publishers Limited, part of Springer Nature https://orcid.org/0000-0001-5951-9358 https://orcid.org/0000-0001-8567-2049 http://dx.doi.org/10.1038/NATURE24265 Nature Creative Commons Attribution 4.0 International License http://creativecommons.org/licenses/by/4.0/ application/pdf Springer Nature Nature |
| spellingShingle | Tukiainen, Taru Villani, Alexandra-Chloé Rivas, Manuel A. Marshall, Jamie L. Satija, Rahul Aguirre, Matt Gauthier, Laura Fleharty, Mark Kirby, Andrew Cummings, Beryl B. Castel, Stephane E. Karczewski, Konrad J. Aguet, François Byrnes, Andrea Aguet, François Ardlie, Kristin G. Cummings, Beryl B. Gelfand, Ellen T. Getz, Gad Hadley, Kane Handsaker, Robert E. Huang, Katherine H. Kashin, Seva Karczewski, Konrad J. Lek, Monkol Li, Xiao MacArthur, Daniel G. Yen, Angela Regev, Aviv Landscape of X chromosome inactivation across human tissues |
| title | Landscape of X chromosome inactivation across human tissues |
| title_full | Landscape of X chromosome inactivation across human tissues |
| title_fullStr | Landscape of X chromosome inactivation across human tissues |
| title_full_unstemmed | Landscape of X chromosome inactivation across human tissues |
| title_short | Landscape of X chromosome inactivation across human tissues |
| title_sort | landscape of x chromosome inactivation across human tissues |
| url | http://hdl.handle.net/1721.1/116808 https://orcid.org/0000-0001-5951-9358 https://orcid.org/0000-0001-8567-2049 |
| work_keys_str_mv | AT tukiainentaru landscapeofxchromosomeinactivationacrosshumantissues AT villanialexandrachloe landscapeofxchromosomeinactivationacrosshumantissues AT rivasmanuela landscapeofxchromosomeinactivationacrosshumantissues AT marshalljamiel landscapeofxchromosomeinactivationacrosshumantissues AT satijarahul landscapeofxchromosomeinactivationacrosshumantissues AT aguirrematt landscapeofxchromosomeinactivationacrosshumantissues AT gauthierlaura landscapeofxchromosomeinactivationacrosshumantissues AT flehartymark landscapeofxchromosomeinactivationacrosshumantissues AT kirbyandrew landscapeofxchromosomeinactivationacrosshumantissues AT cummingsberylb landscapeofxchromosomeinactivationacrosshumantissues AT castelstephanee landscapeofxchromosomeinactivationacrosshumantissues AT karczewskikonradj landscapeofxchromosomeinactivationacrosshumantissues AT aguetfrancois landscapeofxchromosomeinactivationacrosshumantissues AT byrnesandrea landscapeofxchromosomeinactivationacrosshumantissues AT aguetfrancois landscapeofxchromosomeinactivationacrosshumantissues AT ardliekristing landscapeofxchromosomeinactivationacrosshumantissues AT cummingsberylb landscapeofxchromosomeinactivationacrosshumantissues AT gelfandellent landscapeofxchromosomeinactivationacrosshumantissues AT getzgad landscapeofxchromosomeinactivationacrosshumantissues AT hadleykane landscapeofxchromosomeinactivationacrosshumantissues AT handsakerroberte landscapeofxchromosomeinactivationacrosshumantissues AT huangkatherineh landscapeofxchromosomeinactivationacrosshumantissues AT kashinseva landscapeofxchromosomeinactivationacrosshumantissues AT karczewskikonradj landscapeofxchromosomeinactivationacrosshumantissues AT lekmonkol landscapeofxchromosomeinactivationacrosshumantissues AT lixiao landscapeofxchromosomeinactivationacrosshumantissues AT macarthurdanielg landscapeofxchromosomeinactivationacrosshumantissues AT yenangela landscapeofxchromosomeinactivationacrosshumantissues AT regevaviv landscapeofxchromosomeinactivationacrosshumantissues |