Erosion of Dosage Compensation Impacts Human iPSC Disease Modeling

Although distinct human induced pluripotent stem cell (hiPSC) lines can display considerable epigenetic variation, it has been unclear whether such variability impacts their utility for disease modeling. Here, we show that although low-passage female hiPSCs retain the inactive X chromosome of the so...

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Published in	Cell stem cell Vol. 10; no. 5; pp. 595 - 609
Main Authors	Mekhoubad, Shila, Bock, Christoph, de Boer, A. Sophie, Kiskinis, Evangelos, Meissner, Alexander, Eggan, Kevin
Format	Journal Article
Language	English
Published	Cambridge, MA Elsevier Inc 04.05.2012 Cell Press
Subjects	anthropogenic activities Biological and medical sciences Cell differentiation, maturation, development, hematopoiesis Cell physiology Cells, Cultured Chromosomes, Human, X - genetics DNA Methylation Dosage Compensation, Genetic epigenetics Female females Fundamental and applied biological sciences. Psychology genes Genomic Instability Histones - metabolism Humans Induced Pluripotent Stem Cells - metabolism Induced Pluripotent Stem Cells - pathology Lesch-Nyhan Syndrome - genetics Lesch-Nyhan Syndrome - pathology Lesch-Nyhan Syndrome - physiopathology Models, Biological Molecular and cellular biology RNA, Long Noncoding RNA, Untranslated - genetics somatic cells stem cells transcription (genetics) X chromosome Human Gene dosage Dosage compensation Modeling
Online Access	Get full text
ISSN	1934-5909 1875-9777 1875-9777
DOI	10.1016/j.stem.2012.02.014

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Abstract	Although distinct human induced pluripotent stem cell (hiPSC) lines can display considerable epigenetic variation, it has been unclear whether such variability impacts their utility for disease modeling. Here, we show that although low-passage female hiPSCs retain the inactive X chromosome of the somatic cell they are derived from, over time in culture they undergo an “erosion” of X chromosome inactivation (XCI). This erosion of XCI is characterized by loss of XIST expression and foci of H3-K27-trimethylation, as well as transcriptional derepression of genes on the inactive X that cannot be reversed by either differentiation or further reprogramming. We specifically demonstrate that erosion of XCI has a significant impact on the use of female hiPSCs for modeling Lesch-Nyhan syndrome. However, our finding that most genes subject to XCI are derepressed by this erosion of XCI suggests that it should be a significant consideration when selecting hiPSC lines for modeling any disease. [Display omitted] ► hiPSCs can produce a robust model for the study of Lesch-Nyhan syndrome (LNS) ► Female hiPSCs undergo transcriptional derepression of the inactive X (Xi) ► As derepression of Xi occurs, the LNS phenotype in female carrier lines is lost ► Erosion of dosage compensation effects most X-linked loci in female hiPSC and hESC lines
AbstractList	Although distinct human induced pluripotent stem cell (hiPSC) lines can display considerable epigenetic variation, it has been unclear if such variability impacts their utility for disease modeling. Here, we show that although low passage female hiPSCs retain the inactive X-chromosome of the somatic cell they are derived from, over time in culture they undergo an “erosion” of X-chromosome inactivation (XCI). This erosion of XCI is characterized by loss of XIST expression and foci of H3-K27-trimethylation, as well as transcriptional de-repression of genes on the inactive X that cannot be reversed by either differentiation or further reprogramming. We specifically demonstrate that erosion of XCI has a significant impact on the use of female hiPSCs for modeling Lesch-Nyhan syndrome. However, our finding that most genes subject to XCI are de-repressed by this erosion of XCI suggests that it should be a significant consideration when selecting hiPSC lines for modeling any disease. Although distinct human induced pluripotent stem cell (hiPSC) lines can display considerable epigenetic variation, it has been unclear whether such variability impacts their utility for disease modeling. Here, we show that although low-passage female hiPSCs retain the inactive X chromosome of the somatic cell they are derived from, over time in culture they undergo an "erosion" of X chromosome inactivation (XCI). This erosion of XCI is characterized by loss of XIST expression and foci of H3-K27-trimethylation, as well as transcriptional derepression of genes on the inactive X that cannot be reversed by either differentiation or further reprogramming. We specifically demonstrate that erosion of XCI has a significant impact on the use of female hiPSCs for modeling Lesch-Nyhan syndrome. However, our finding that most genes subject to XCI are derepressed by this erosion of XCI suggests that it should be a significant consideration when selecting hiPSC lines for modeling any disease. Although distinct human induced pluripotent stem cell (hiPSC) lines can display considerable epigenetic variation, it has been unclear whether such variability impacts their utility for disease modeling. Here, we show that although low-passage female hiPSCs retain the inactive X chromosome of the somatic cell they are derived from, over time in culture they undergo an aerosiona of X chromosome inactivation (XCI). This erosion of XCI is characterized by loss of XIST expression and foci of H3-K27-trimethylation, as well as transcriptional derepression of genes on the inactive X that cannot be reversed by either differentiation or further reprogramming. We specifically demonstrate that erosion of XCI has a significant impact on the use of female hiPSCs for modeling Lesch-Nyhan syndrome. However, our finding that most genes subject to XCI are derepressed by this erosion of XCI suggests that it should be a significant consideration when selecting hiPSC lines for modeling any disease. Although distinct human induced pluripotent stem cell (hiPSC) lines can display considerable epigenetic variation, it has been unclear whether such variability impacts their utility for disease modeling. Here, we show that although low-passage female hiPSCs retain the inactive X chromosome of the somatic cell they are derived from, over time in culture they undergo an “erosion” of X chromosome inactivation (XCI). This erosion of XCI is characterized by loss of XIST expression and foci of H3-K27-trimethylation, as well as transcriptional derepression of genes on the inactive X that cannot be reversed by either differentiation or further reprogramming. We specifically demonstrate that erosion of XCI has a significant impact on the use of female hiPSCs for modeling Lesch-Nyhan syndrome. However, our finding that most genes subject to XCI are derepressed by this erosion of XCI suggests that it should be a significant consideration when selecting hiPSC lines for modeling any disease. [Display omitted] ► hiPSCs can produce a robust model for the study of Lesch-Nyhan syndrome (LNS) ► Female hiPSCs undergo transcriptional derepression of the inactive X (Xi) ► As derepression of Xi occurs, the LNS phenotype in female carrier lines is lost ► Erosion of dosage compensation effects most X-linked loci in female hiPSC and hESC lines Although distinct human induced pluripotent stem cell (hiPSC) lines can display considerable epigenetic variation, it has been unclear whether such variability impacts their utility for disease modeling. Here, we show that although low-passage female hiPSCs retain the inactive X chromosome of the somatic cell they are derived from, over time in culture they undergo an "erosion" of X chromosome inactivation (XCI). This erosion of XCI is characterized by loss of XIST expression and foci of H3-K27-trimethylation, as well as transcriptional derepression of genes on the inactive X that cannot be reversed by either differentiation or further reprogramming. We specifically demonstrate that erosion of XCI has a significant impact on the use of female hiPSCs for modeling Lesch-Nyhan syndrome. However, our finding that most genes subject to XCI are derepressed by this erosion of XCI suggests that it should be a significant consideration when selecting hiPSC lines for modeling any disease.Although distinct human induced pluripotent stem cell (hiPSC) lines can display considerable epigenetic variation, it has been unclear whether such variability impacts their utility for disease modeling. Here, we show that although low-passage female hiPSCs retain the inactive X chromosome of the somatic cell they are derived from, over time in culture they undergo an "erosion" of X chromosome inactivation (XCI). This erosion of XCI is characterized by loss of XIST expression and foci of H3-K27-trimethylation, as well as transcriptional derepression of genes on the inactive X that cannot be reversed by either differentiation or further reprogramming. We specifically demonstrate that erosion of XCI has a significant impact on the use of female hiPSCs for modeling Lesch-Nyhan syndrome. However, our finding that most genes subject to XCI are derepressed by this erosion of XCI suggests that it should be a significant consideration when selecting hiPSC lines for modeling any disease.
Author	Mekhoubad, Shila Kiskinis, Evangelos de Boer, A. Sophie Bock, Christoph Meissner, Alexander Eggan, Kevin
AuthorAffiliation	6 Department of Anatomy & Embryology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands 5 Max Planck Institute for Informatics, 66123 Saarbrucken, Germany 3 Department of Molecular and Cellular Biology Harvard University, Cambridge, MA 02138, USA 4 The Broad Institute, Cambridge, MA 02142, USA 1 The Harvard Stem Cell Institute, Department of Stem Cell and Regenerative Biology 2 The Howard Hughes Medical Institute
AuthorAffiliation_xml	– name: 3 Department of Molecular and Cellular Biology Harvard University, Cambridge, MA 02138, USA – name: 4 The Broad Institute, Cambridge, MA 02142, USA – name: 5 Max Planck Institute for Informatics, 66123 Saarbrucken, Germany – name: 1 The Harvard Stem Cell Institute, Department of Stem Cell and Regenerative Biology – name: 6 Department of Anatomy & Embryology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands – name: 2 The Howard Hughes Medical Institute
Author_xml	– sequence: 1 givenname: Shila surname: Mekhoubad fullname: Mekhoubad, Shila organization: The Harvard Stem Cell Institute, Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA – sequence: 2 givenname: Christoph surname: Bock fullname: Bock, Christoph organization: The Harvard Stem Cell Institute, Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA – sequence: 3 givenname: A. Sophie surname: de Boer fullname: de Boer, A. Sophie organization: The Harvard Stem Cell Institute, Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA – sequence: 4 givenname: Evangelos surname: Kiskinis fullname: Kiskinis, Evangelos organization: The Harvard Stem Cell Institute, Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA – sequence: 5 givenname: Alexander surname: Meissner fullname: Meissner, Alexander email: alexander_meissner@harvard.edu organization: The Harvard Stem Cell Institute, Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA – sequence: 6 givenname: Kevin surname: Eggan fullname: Eggan, Kevin email: keggan@scrb.harvard.edu organization: The Harvard Stem Cell Institute, Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA
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Snippet	Although distinct human induced pluripotent stem cell (hiPSC) lines can display considerable epigenetic variation, it has been unclear whether such variability... Although distinct human induced pluripotent stem cell (hiPSC) lines can display considerable epigenetic variation, it has been unclear if such variability...
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SubjectTerms	anthropogenic activities Biological and medical sciences Cell differentiation, maturation, development, hematopoiesis Cell physiology Cells, Cultured Chromosomes, Human, X - genetics DNA Methylation Dosage Compensation, Genetic epigenetics Female females Fundamental and applied biological sciences. Psychology genes Genomic Instability Histones - metabolism Humans Induced Pluripotent Stem Cells - metabolism Induced Pluripotent Stem Cells - pathology Lesch-Nyhan Syndrome - genetics Lesch-Nyhan Syndrome - pathology Lesch-Nyhan Syndrome - physiopathology Models, Biological Molecular and cellular biology RNA, Long Noncoding RNA, Untranslated - genetics somatic cells stem cells transcription (genetics) X chromosome
Title	Erosion of Dosage Compensation Impacts Human iPSC Disease Modeling
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