X-chromosome inactivation in human iPSCs provides insight into X-regulated gene expression in autosomes

Background Variation in X chromosome inactivation (XCI) in human-induced pluripotent stem cells (hiPSCs) can impact their ability to model biological sex biases. The gene-wise landscape of X chromosome gene dosage remains unresolved in female hiPSCs. To characterize patterns of de-repression and esc...
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Autor*in:	Topa, Hande [verfasserIn] Benoit-Pilven, Clara [verfasserIn] Tukiainen, Taru [verfasserIn] Pietiläinen, Olli [verfasserIn]

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2024

Schlagwörter:	X chromosome inactivation hiPSC Sex differences RNA-seq Allele-specific expression -bound autosomal genes X chromosome-regulated gene expression

Anmerkung:	© The Author(s) 2024

Übergeordnetes Werk:	Enthalten in: Genome biology - BioMed Central, 2000, 25(2024), 1 vom: 31. Mai
Übergeordnetes Werk:	volume:25 ; year:2024 ; number:1 ; day:31 ; month:05

Links:	Volltext

DOI / URN:	10.1186/s13059-024-03286-8

Katalog-ID:	SPR056076754

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520			\|a Background Variation in X chromosome inactivation (XCI) in human-induced pluripotent stem cells (hiPSCs) can impact their ability to model biological sex biases. The gene-wise landscape of X chromosome gene dosage remains unresolved in female hiPSCs. To characterize patterns of de-repression and escape from inactivation, we performed a systematic survey of allele specific expression in 165 female hiPSC lines. Results XCI erosion is non-random and primarily affects genes that escape XCI in human tissues. Individual genes and cell lines vary in the frequency and degree of de-repression. Bi-allelic expression increases gradually after modest decrease of XIST in cultures, whose loss is commonly used to mark lines with eroded XCI. We identify three clusters of female lines at different stages of XCI. Increased XCI erosion amplifies female-biased expression at hypomethylated sites and regions normally occupied by repressive histone marks, lowering male-biased differences in the X chromosome. In autosomes, erosion modifies sex differences in a dose-dependent way. Male-biased genes are enriched for hypermethylated regions, and de-repression of XIST-bound autosomal genes in female lines attenuates normal male-biased gene expression in eroded lines. XCI erosion can compensate for a dominant loss of function effect in several disease genes. Conclusions We present a comprehensive view of X chromosome gene dosage in hiPSCs and implicate a direct mechanism for XCI erosion in regulating autosomal gene expression in trans. The uncommon and variable reactivation of X chromosome genes in female hiPSCs can provide insight into X chromosome’s role in regulating gene expression and sex differences in humans.
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allfields	10.1186/s13059-024-03286-8 doi (DE-627)SPR056076754 (SPR)s13059-024-03286-8-e DE-627 ger DE-627 rakwb eng 570 VZ BIODIV DE-30 fid 42.13 bkl 42.20 bkl Topa, Hande verfasserin aut X-chromosome inactivation in human iPSCs provides insight into X-regulated gene expression in autosomes 2024 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2024 Background Variation in X chromosome inactivation (XCI) in human-induced pluripotent stem cells (hiPSCs) can impact their ability to model biological sex biases. The gene-wise landscape of X chromosome gene dosage remains unresolved in female hiPSCs. To characterize patterns of de-repression and escape from inactivation, we performed a systematic survey of allele specific expression in 165 female hiPSC lines. Results XCI erosion is non-random and primarily affects genes that escape XCI in human tissues. Individual genes and cell lines vary in the frequency and degree of de-repression. Bi-allelic expression increases gradually after modest decrease of XIST in cultures, whose loss is commonly used to mark lines with eroded XCI. We identify three clusters of female lines at different stages of XCI. Increased XCI erosion amplifies female-biased expression at hypomethylated sites and regions normally occupied by repressive histone marks, lowering male-biased differences in the X chromosome. In autosomes, erosion modifies sex differences in a dose-dependent way. Male-biased genes are enriched for hypermethylated regions, and de-repression of XIST-bound autosomal genes in female lines attenuates normal male-biased gene expression in eroded lines. XCI erosion can compensate for a dominant loss of function effect in several disease genes. Conclusions We present a comprehensive view of X chromosome gene dosage in hiPSCs and implicate a direct mechanism for XCI erosion in regulating autosomal gene expression in trans. The uncommon and variable reactivation of X chromosome genes in female hiPSCs can provide insight into X chromosome’s role in regulating gene expression and sex differences in humans. X chromosome inactivation (dpeaa)DE-He213 hiPSC (dpeaa)DE-He213 Sex differences (dpeaa)DE-He213 RNA-seq (dpeaa)DE-He213 Allele-specific expression (dpeaa)DE-He213 -bound autosomal genes (dpeaa)DE-He213 X chromosome-regulated gene expression (dpeaa)DE-He213 Benoit-Pilven, Clara verfasserin aut Tukiainen, Taru verfasserin aut Pietiläinen, Olli verfasserin (orcid)0000-0003-4387-1861 aut Enthalten in Genome biology BioMed Central, 2000 25(2024), 1 vom: 31. Mai (DE-627)326173617 (DE-600)2040529-7 1474-760X nnns volume:25 year:2024 number:1 day:31 month:05 https://dx.doi.org/10.1186/s13059-024-03286-8 X:SPRINGER Resolving-System kostenfrei Volltext SYSFLAG_0 GBV_SPRINGER FID-BIODIV SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 42.13 VZ 42.20 VZ AR 25 2024 1 31 05
spelling	10.1186/s13059-024-03286-8 doi (DE-627)SPR056076754 (SPR)s13059-024-03286-8-e DE-627 ger DE-627 rakwb eng 570 VZ BIODIV DE-30 fid 42.13 bkl 42.20 bkl Topa, Hande verfasserin aut X-chromosome inactivation in human iPSCs provides insight into X-regulated gene expression in autosomes 2024 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2024 Background Variation in X chromosome inactivation (XCI) in human-induced pluripotent stem cells (hiPSCs) can impact their ability to model biological sex biases. The gene-wise landscape of X chromosome gene dosage remains unresolved in female hiPSCs. To characterize patterns of de-repression and escape from inactivation, we performed a systematic survey of allele specific expression in 165 female hiPSC lines. Results XCI erosion is non-random and primarily affects genes that escape XCI in human tissues. Individual genes and cell lines vary in the frequency and degree of de-repression. Bi-allelic expression increases gradually after modest decrease of XIST in cultures, whose loss is commonly used to mark lines with eroded XCI. We identify three clusters of female lines at different stages of XCI. Increased XCI erosion amplifies female-biased expression at hypomethylated sites and regions normally occupied by repressive histone marks, lowering male-biased differences in the X chromosome. In autosomes, erosion modifies sex differences in a dose-dependent way. Male-biased genes are enriched for hypermethylated regions, and de-repression of XIST-bound autosomal genes in female lines attenuates normal male-biased gene expression in eroded lines. XCI erosion can compensate for a dominant loss of function effect in several disease genes. Conclusions We present a comprehensive view of X chromosome gene dosage in hiPSCs and implicate a direct mechanism for XCI erosion in regulating autosomal gene expression in trans. The uncommon and variable reactivation of X chromosome genes in female hiPSCs can provide insight into X chromosome’s role in regulating gene expression and sex differences in humans. X chromosome inactivation (dpeaa)DE-He213 hiPSC (dpeaa)DE-He213 Sex differences (dpeaa)DE-He213 RNA-seq (dpeaa)DE-He213 Allele-specific expression (dpeaa)DE-He213 -bound autosomal genes (dpeaa)DE-He213 X chromosome-regulated gene expression (dpeaa)DE-He213 Benoit-Pilven, Clara verfasserin aut Tukiainen, Taru verfasserin aut Pietiläinen, Olli verfasserin (orcid)0000-0003-4387-1861 aut Enthalten in Genome biology BioMed Central, 2000 25(2024), 1 vom: 31. Mai (DE-627)326173617 (DE-600)2040529-7 1474-760X nnns volume:25 year:2024 number:1 day:31 month:05 https://dx.doi.org/10.1186/s13059-024-03286-8 X:SPRINGER Resolving-System kostenfrei Volltext SYSFLAG_0 GBV_SPRINGER FID-BIODIV SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 42.13 VZ 42.20 VZ AR 25 2024 1 31 05
allfields_unstemmed	10.1186/s13059-024-03286-8 doi (DE-627)SPR056076754 (SPR)s13059-024-03286-8-e DE-627 ger DE-627 rakwb eng 570 VZ BIODIV DE-30 fid 42.13 bkl 42.20 bkl Topa, Hande verfasserin aut X-chromosome inactivation in human iPSCs provides insight into X-regulated gene expression in autosomes 2024 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2024 Background Variation in X chromosome inactivation (XCI) in human-induced pluripotent stem cells (hiPSCs) can impact their ability to model biological sex biases. The gene-wise landscape of X chromosome gene dosage remains unresolved in female hiPSCs. To characterize patterns of de-repression and escape from inactivation, we performed a systematic survey of allele specific expression in 165 female hiPSC lines. Results XCI erosion is non-random and primarily affects genes that escape XCI in human tissues. Individual genes and cell lines vary in the frequency and degree of de-repression. Bi-allelic expression increases gradually after modest decrease of XIST in cultures, whose loss is commonly used to mark lines with eroded XCI. We identify three clusters of female lines at different stages of XCI. Increased XCI erosion amplifies female-biased expression at hypomethylated sites and regions normally occupied by repressive histone marks, lowering male-biased differences in the X chromosome. In autosomes, erosion modifies sex differences in a dose-dependent way. Male-biased genes are enriched for hypermethylated regions, and de-repression of XIST-bound autosomal genes in female lines attenuates normal male-biased gene expression in eroded lines. XCI erosion can compensate for a dominant loss of function effect in several disease genes. Conclusions We present a comprehensive view of X chromosome gene dosage in hiPSCs and implicate a direct mechanism for XCI erosion in regulating autosomal gene expression in trans. The uncommon and variable reactivation of X chromosome genes in female hiPSCs can provide insight into X chromosome’s role in regulating gene expression and sex differences in humans. X chromosome inactivation (dpeaa)DE-He213 hiPSC (dpeaa)DE-He213 Sex differences (dpeaa)DE-He213 RNA-seq (dpeaa)DE-He213 Allele-specific expression (dpeaa)DE-He213 -bound autosomal genes (dpeaa)DE-He213 X chromosome-regulated gene expression (dpeaa)DE-He213 Benoit-Pilven, Clara verfasserin aut Tukiainen, Taru verfasserin aut Pietiläinen, Olli verfasserin (orcid)0000-0003-4387-1861 aut Enthalten in Genome biology BioMed Central, 2000 25(2024), 1 vom: 31. Mai (DE-627)326173617 (DE-600)2040529-7 1474-760X nnns volume:25 year:2024 number:1 day:31 month:05 https://dx.doi.org/10.1186/s13059-024-03286-8 X:SPRINGER Resolving-System kostenfrei Volltext SYSFLAG_0 GBV_SPRINGER FID-BIODIV SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 42.13 VZ 42.20 VZ AR 25 2024 1 31 05
allfieldsGer	10.1186/s13059-024-03286-8 doi (DE-627)SPR056076754 (SPR)s13059-024-03286-8-e DE-627 ger DE-627 rakwb eng 570 VZ BIODIV DE-30 fid 42.13 bkl 42.20 bkl Topa, Hande verfasserin aut X-chromosome inactivation in human iPSCs provides insight into X-regulated gene expression in autosomes 2024 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2024 Background Variation in X chromosome inactivation (XCI) in human-induced pluripotent stem cells (hiPSCs) can impact their ability to model biological sex biases. The gene-wise landscape of X chromosome gene dosage remains unresolved in female hiPSCs. To characterize patterns of de-repression and escape from inactivation, we performed a systematic survey of allele specific expression in 165 female hiPSC lines. Results XCI erosion is non-random and primarily affects genes that escape XCI in human tissues. Individual genes and cell lines vary in the frequency and degree of de-repression. Bi-allelic expression increases gradually after modest decrease of XIST in cultures, whose loss is commonly used to mark lines with eroded XCI. We identify three clusters of female lines at different stages of XCI. Increased XCI erosion amplifies female-biased expression at hypomethylated sites and regions normally occupied by repressive histone marks, lowering male-biased differences in the X chromosome. In autosomes, erosion modifies sex differences in a dose-dependent way. Male-biased genes are enriched for hypermethylated regions, and de-repression of XIST-bound autosomal genes in female lines attenuates normal male-biased gene expression in eroded lines. XCI erosion can compensate for a dominant loss of function effect in several disease genes. Conclusions We present a comprehensive view of X chromosome gene dosage in hiPSCs and implicate a direct mechanism for XCI erosion in regulating autosomal gene expression in trans. The uncommon and variable reactivation of X chromosome genes in female hiPSCs can provide insight into X chromosome’s role in regulating gene expression and sex differences in humans. X chromosome inactivation (dpeaa)DE-He213 hiPSC (dpeaa)DE-He213 Sex differences (dpeaa)DE-He213 RNA-seq (dpeaa)DE-He213 Allele-specific expression (dpeaa)DE-He213 -bound autosomal genes (dpeaa)DE-He213 X chromosome-regulated gene expression (dpeaa)DE-He213 Benoit-Pilven, Clara verfasserin aut Tukiainen, Taru verfasserin aut Pietiläinen, Olli verfasserin (orcid)0000-0003-4387-1861 aut Enthalten in Genome biology BioMed Central, 2000 25(2024), 1 vom: 31. Mai (DE-627)326173617 (DE-600)2040529-7 1474-760X nnns volume:25 year:2024 number:1 day:31 month:05 https://dx.doi.org/10.1186/s13059-024-03286-8 X:SPRINGER Resolving-System kostenfrei Volltext SYSFLAG_0 GBV_SPRINGER FID-BIODIV SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 42.13 VZ 42.20 VZ AR 25 2024 1 31 05
allfieldsSound	10.1186/s13059-024-03286-8 doi (DE-627)SPR056076754 (SPR)s13059-024-03286-8-e DE-627 ger DE-627 rakwb eng 570 VZ BIODIV DE-30 fid 42.13 bkl 42.20 bkl Topa, Hande verfasserin aut X-chromosome inactivation in human iPSCs provides insight into X-regulated gene expression in autosomes 2024 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2024 Background Variation in X chromosome inactivation (XCI) in human-induced pluripotent stem cells (hiPSCs) can impact their ability to model biological sex biases. The gene-wise landscape of X chromosome gene dosage remains unresolved in female hiPSCs. To characterize patterns of de-repression and escape from inactivation, we performed a systematic survey of allele specific expression in 165 female hiPSC lines. Results XCI erosion is non-random and primarily affects genes that escape XCI in human tissues. Individual genes and cell lines vary in the frequency and degree of de-repression. Bi-allelic expression increases gradually after modest decrease of XIST in cultures, whose loss is commonly used to mark lines with eroded XCI. We identify three clusters of female lines at different stages of XCI. Increased XCI erosion amplifies female-biased expression at hypomethylated sites and regions normally occupied by repressive histone marks, lowering male-biased differences in the X chromosome. In autosomes, erosion modifies sex differences in a dose-dependent way. Male-biased genes are enriched for hypermethylated regions, and de-repression of XIST-bound autosomal genes in female lines attenuates normal male-biased gene expression in eroded lines. XCI erosion can compensate for a dominant loss of function effect in several disease genes. Conclusions We present a comprehensive view of X chromosome gene dosage in hiPSCs and implicate a direct mechanism for XCI erosion in regulating autosomal gene expression in trans. The uncommon and variable reactivation of X chromosome genes in female hiPSCs can provide insight into X chromosome’s role in regulating gene expression and sex differences in humans. X chromosome inactivation (dpeaa)DE-He213 hiPSC (dpeaa)DE-He213 Sex differences (dpeaa)DE-He213 RNA-seq (dpeaa)DE-He213 Allele-specific expression (dpeaa)DE-He213 -bound autosomal genes (dpeaa)DE-He213 X chromosome-regulated gene expression (dpeaa)DE-He213 Benoit-Pilven, Clara verfasserin aut Tukiainen, Taru verfasserin aut Pietiläinen, Olli verfasserin (orcid)0000-0003-4387-1861 aut Enthalten in Genome biology BioMed Central, 2000 25(2024), 1 vom: 31. Mai (DE-627)326173617 (DE-600)2040529-7 1474-760X nnns volume:25 year:2024 number:1 day:31 month:05 https://dx.doi.org/10.1186/s13059-024-03286-8 X:SPRINGER Resolving-System kostenfrei Volltext SYSFLAG_0 GBV_SPRINGER FID-BIODIV SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 42.13 VZ 42.20 VZ AR 25 2024 1 31 05
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author	Topa, Hande
spellingShingle	Topa, Hande ddc 570 fid BIODIV bkl 42.13 bkl 42.20 misc X chromosome inactivation misc hiPSC misc Sex differences misc RNA-seq misc Allele-specific expression misc -bound autosomal genes misc X chromosome-regulated gene expression X-chromosome inactivation in human iPSCs provides insight into X-regulated gene expression in autosomes
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topic_title	570 VZ BIODIV DE-30 fid 42.13 bkl 42.20 bkl X-chromosome inactivation in human iPSCs provides insight into X-regulated gene expression in autosomes X chromosome inactivation (dpeaa)DE-He213 hiPSC (dpeaa)DE-He213 Sex differences (dpeaa)DE-He213 RNA-seq (dpeaa)DE-He213 Allele-specific expression (dpeaa)DE-He213 -bound autosomal genes (dpeaa)DE-He213 X chromosome-regulated gene expression (dpeaa)DE-He213
topic	ddc 570 fid BIODIV bkl 42.13 bkl 42.20 misc X chromosome inactivation misc hiPSC misc Sex differences misc RNA-seq misc Allele-specific expression misc -bound autosomal genes misc X chromosome-regulated gene expression
topic_unstemmed	ddc 570 fid BIODIV bkl 42.13 bkl 42.20 misc X chromosome inactivation misc hiPSC misc Sex differences misc RNA-seq misc Allele-specific expression misc -bound autosomal genes misc X chromosome-regulated gene expression
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title	X-chromosome inactivation in human iPSCs provides insight into X-regulated gene expression in autosomes
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title_full	X-chromosome inactivation in human iPSCs provides insight into X-regulated gene expression in autosomes
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title_sort	x-chromosome inactivation in human ipscs provides insight into x-regulated gene expression in autosomes
title_auth	X-chromosome inactivation in human iPSCs provides insight into X-regulated gene expression in autosomes
abstract	Background Variation in X chromosome inactivation (XCI) in human-induced pluripotent stem cells (hiPSCs) can impact their ability to model biological sex biases. The gene-wise landscape of X chromosome gene dosage remains unresolved in female hiPSCs. To characterize patterns of de-repression and escape from inactivation, we performed a systematic survey of allele specific expression in 165 female hiPSC lines. Results XCI erosion is non-random and primarily affects genes that escape XCI in human tissues. Individual genes and cell lines vary in the frequency and degree of de-repression. Bi-allelic expression increases gradually after modest decrease of XIST in cultures, whose loss is commonly used to mark lines with eroded XCI. We identify three clusters of female lines at different stages of XCI. Increased XCI erosion amplifies female-biased expression at hypomethylated sites and regions normally occupied by repressive histone marks, lowering male-biased differences in the X chromosome. In autosomes, erosion modifies sex differences in a dose-dependent way. Male-biased genes are enriched for hypermethylated regions, and de-repression of XIST-bound autosomal genes in female lines attenuates normal male-biased gene expression in eroded lines. XCI erosion can compensate for a dominant loss of function effect in several disease genes. Conclusions We present a comprehensive view of X chromosome gene dosage in hiPSCs and implicate a direct mechanism for XCI erosion in regulating autosomal gene expression in trans. The uncommon and variable reactivation of X chromosome genes in female hiPSCs can provide insight into X chromosome’s role in regulating gene expression and sex differences in humans. © The Author(s) 2024
abstractGer	Background Variation in X chromosome inactivation (XCI) in human-induced pluripotent stem cells (hiPSCs) can impact their ability to model biological sex biases. The gene-wise landscape of X chromosome gene dosage remains unresolved in female hiPSCs. To characterize patterns of de-repression and escape from inactivation, we performed a systematic survey of allele specific expression in 165 female hiPSC lines. Results XCI erosion is non-random and primarily affects genes that escape XCI in human tissues. Individual genes and cell lines vary in the frequency and degree of de-repression. Bi-allelic expression increases gradually after modest decrease of XIST in cultures, whose loss is commonly used to mark lines with eroded XCI. We identify three clusters of female lines at different stages of XCI. Increased XCI erosion amplifies female-biased expression at hypomethylated sites and regions normally occupied by repressive histone marks, lowering male-biased differences in the X chromosome. In autosomes, erosion modifies sex differences in a dose-dependent way. Male-biased genes are enriched for hypermethylated regions, and de-repression of XIST-bound autosomal genes in female lines attenuates normal male-biased gene expression in eroded lines. XCI erosion can compensate for a dominant loss of function effect in several disease genes. Conclusions We present a comprehensive view of X chromosome gene dosage in hiPSCs and implicate a direct mechanism for XCI erosion in regulating autosomal gene expression in trans. The uncommon and variable reactivation of X chromosome genes in female hiPSCs can provide insight into X chromosome’s role in regulating gene expression and sex differences in humans. © The Author(s) 2024
abstract_unstemmed	Background Variation in X chromosome inactivation (XCI) in human-induced pluripotent stem cells (hiPSCs) can impact their ability to model biological sex biases. The gene-wise landscape of X chromosome gene dosage remains unresolved in female hiPSCs. To characterize patterns of de-repression and escape from inactivation, we performed a systematic survey of allele specific expression in 165 female hiPSC lines. Results XCI erosion is non-random and primarily affects genes that escape XCI in human tissues. Individual genes and cell lines vary in the frequency and degree of de-repression. Bi-allelic expression increases gradually after modest decrease of XIST in cultures, whose loss is commonly used to mark lines with eroded XCI. We identify three clusters of female lines at different stages of XCI. Increased XCI erosion amplifies female-biased expression at hypomethylated sites and regions normally occupied by repressive histone marks, lowering male-biased differences in the X chromosome. In autosomes, erosion modifies sex differences in a dose-dependent way. Male-biased genes are enriched for hypermethylated regions, and de-repression of XIST-bound autosomal genes in female lines attenuates normal male-biased gene expression in eroded lines. XCI erosion can compensate for a dominant loss of function effect in several disease genes. Conclusions We present a comprehensive view of X chromosome gene dosage in hiPSCs and implicate a direct mechanism for XCI erosion in regulating autosomal gene expression in trans. The uncommon and variable reactivation of X chromosome genes in female hiPSCs can provide insight into X chromosome’s role in regulating gene expression and sex differences in humans. © The Author(s) 2024
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title_short	X-chromosome inactivation in human iPSCs provides insight into X-regulated gene expression in autosomes
url	https://dx.doi.org/10.1186/s13059-024-03286-8
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author2	Benoit-Pilven, Clara Tukiainen, Taru Pietiläinen, Olli
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The gene-wise landscape of X chromosome gene dosage remains unresolved in female hiPSCs. To characterize patterns of de-repression and escape from inactivation, we performed a systematic survey of allele specific expression in 165 female hiPSC lines. Results XCI erosion is non-random and primarily affects genes that escape XCI in human tissues. Individual genes and cell lines vary in the frequency and degree of de-repression. Bi-allelic expression increases gradually after modest decrease of XIST in cultures, whose loss is commonly used to mark lines with eroded XCI. We identify three clusters of female lines at different stages of XCI. Increased XCI erosion amplifies female-biased expression at hypomethylated sites and regions normally occupied by repressive histone marks, lowering male-biased differences in the X chromosome. In autosomes, erosion modifies sex differences in a dose-dependent way. Male-biased genes are enriched for hypermethylated regions, and de-repression of XIST-bound autosomal genes in female lines attenuates normal male-biased gene expression in eroded lines. XCI erosion can compensate for a dominant loss of function effect in several disease genes. Conclusions We present a comprehensive view of X chromosome gene dosage in hiPSCs and implicate a direct mechanism for XCI erosion in regulating autosomal gene expression in trans. 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X-chromosome inactivation in human iPSCs provides insight into X-regulated gene expression in autosomes

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