B cell stimulation changes the structure and higher-order organization of the inactive X chromosome

Isabel Sierra; Natalie E. Toothacre; Robin H. van der Weide; Claudia D. Lovell; Son C. Nguyen; R. Jordan Barnett; Ashley L. Cook; Han Seul Ryu; Sarah Pyfrom; Harrison Wang; Daniel Beiting; Jennifer E. Philips-Cremins; Eric F. Joyce; Montserrat C. Anguera

doi:10.1016/j.celrep.2025.115351

B cell stimulation changes the structure and higher-order organization of the inactive X chromosome

Isabel Sierra, Natalie E. Toothacre, Robin H. van der Weide, Claudia D. Lovell, Son C. Nguyen, R. Jordan Barnett, Ashley L. Cook, Han Seul Ryu, Sarah Pyfrom, Harrison Wang, Daniel Beiting, Jennifer E. Philips-Cremins, Eric F. Joyce, Montserrat C. Anguera^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

X chromosome inactivation (XCI) equalizes X-linked gene expression between sexes. B cells exhibit dynamic XCI, with Xist RNA/heterochromatic marks absent on the inactive X (Xi) in naive B cells but returning following mitogenic stimulation. The impact of dynamic XCI on Xi structure and maintenance was previously unknown. Here, we find dosage compensation of the Xi with state-specific XCI escape genes in naive and in vitro-activated B cells. Allele-specific OligoPaints indicate similar Xi and active X (Xa) territories in B cells that are less compact than in fibroblasts. Allele-specific Hi-C reveals a lack of TAD-like structures on the Xi of naive B cells and stimulation-induced alterations in TAD-like boundary strength independent of gene expression. Notably, Xist deletion in B cells changes TAD boundaries and large-scale Xi compaction. Altogether, our results uncover B cell-specific Xi plasticity, which could underlie sex-biased biological mechanisms.

Original language	English
Article number	115351
Journal	Cell Reports
Volume	44
Issue number	3
DOIs	https://doi.org/10.1016/j.celrep.2025.115351
Publication status	Published - 25 Mar 2025
Externally published	Yes

Keywords

allele-specific Hi-C
B cell stimulation
B cells
chromosome compartments
chromosome structure
CP: Immunology
CP: Molecular biology
inactive X chromosome
TAD remodeling
topological associated domains
X chromosome inactivation
XCI escape genes
XCI maintenance
Xist RNA

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Sierra, I., Toothacre, N. E., van der Weide, R. H., Lovell, C. D., Nguyen, S. C., Barnett, R. J., Cook, A. L., Ryu, H. S., Pyfrom, S., Wang, H., Beiting, D., Philips-Cremins, J. E., Joyce, E. F., & Anguera, M. C. (2025). B cell stimulation changes the structure and higher-order organization of the inactive X chromosome. Cell Reports, 44(3), Article 115351. https://doi.org/10.1016/j.celrep.2025.115351

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title = "B cell stimulation changes the structure and higher-order organization of the inactive X chromosome",

abstract = "X chromosome inactivation (XCI) equalizes X-linked gene expression between sexes. B cells exhibit dynamic XCI, with Xist RNA/heterochromatic marks absent on the inactive X (Xi) in naive B cells but returning following mitogenic stimulation. The impact of dynamic XCI on Xi structure and maintenance was previously unknown. Here, we find dosage compensation of the Xi with state-specific XCI escape genes in naive and in vitro-activated B cells. Allele-specific OligoPaints indicate similar Xi and active X (Xa) territories in B cells that are less compact than in fibroblasts. Allele-specific Hi-C reveals a lack of TAD-like structures on the Xi of naive B cells and stimulation-induced alterations in TAD-like boundary strength independent of gene expression. Notably, Xist deletion in B cells changes TAD boundaries and large-scale Xi compaction. Altogether, our results uncover B cell-specific Xi plasticity, which could underlie sex-biased biological mechanisms.",

keywords = "allele-specific Hi-C, B cell stimulation, B cells, chromosome compartments, chromosome structure, CP: Immunology, CP: Molecular biology, inactive X chromosome, TAD remodeling, topological associated domains, X chromosome inactivation, XCI escape genes, XCI maintenance, Xist RNA",

author = "Isabel Sierra and Toothacre, {Natalie E.} and {van der Weide}, {Robin H.} and Lovell, {Claudia D.} and Nguyen, {Son C.} and Barnett, {R. Jordan} and Cook, {Ashley L.} and Ryu, {Han Seul} and Sarah Pyfrom and Harrison Wang and Daniel Beiting and Philips-Cremins, {Jennifer E.} and Joyce, {Eric F.} and Anguera, {Montserrat C.}",

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year = "2025",

month = mar,

day = "25",

doi = "10.1016/j.celrep.2025.115351",

language = "English",

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T1 - B cell stimulation changes the structure and higher-order organization of the inactive X chromosome

AU - Sierra, Isabel

AU - Toothacre, Natalie E.

AU - van der Weide, Robin H.

AU - Lovell, Claudia D.

AU - Nguyen, Son C.

AU - Barnett, R. Jordan

AU - Cook, Ashley L.

AU - Ryu, Han Seul

AU - Pyfrom, Sarah

AU - Wang, Harrison

AU - Beiting, Daniel

AU - Philips-Cremins, Jennifer E.

AU - Joyce, Eric F.

AU - Anguera, Montserrat C.

PY - 2025/3/25

Y1 - 2025/3/25

N2 - X chromosome inactivation (XCI) equalizes X-linked gene expression between sexes. B cells exhibit dynamic XCI, with Xist RNA/heterochromatic marks absent on the inactive X (Xi) in naive B cells but returning following mitogenic stimulation. The impact of dynamic XCI on Xi structure and maintenance was previously unknown. Here, we find dosage compensation of the Xi with state-specific XCI escape genes in naive and in vitro-activated B cells. Allele-specific OligoPaints indicate similar Xi and active X (Xa) territories in B cells that are less compact than in fibroblasts. Allele-specific Hi-C reveals a lack of TAD-like structures on the Xi of naive B cells and stimulation-induced alterations in TAD-like boundary strength independent of gene expression. Notably, Xist deletion in B cells changes TAD boundaries and large-scale Xi compaction. Altogether, our results uncover B cell-specific Xi plasticity, which could underlie sex-biased biological mechanisms.

AB - X chromosome inactivation (XCI) equalizes X-linked gene expression between sexes. B cells exhibit dynamic XCI, with Xist RNA/heterochromatic marks absent on the inactive X (Xi) in naive B cells but returning following mitogenic stimulation. The impact of dynamic XCI on Xi structure and maintenance was previously unknown. Here, we find dosage compensation of the Xi with state-specific XCI escape genes in naive and in vitro-activated B cells. Allele-specific OligoPaints indicate similar Xi and active X (Xa) territories in B cells that are less compact than in fibroblasts. Allele-specific Hi-C reveals a lack of TAD-like structures on the Xi of naive B cells and stimulation-induced alterations in TAD-like boundary strength independent of gene expression. Notably, Xist deletion in B cells changes TAD boundaries and large-scale Xi compaction. Altogether, our results uncover B cell-specific Xi plasticity, which could underlie sex-biased biological mechanisms.

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KW - B cell stimulation

KW - B cells

KW - chromosome compartments

KW - chromosome structure

KW - CP: Immunology

KW - CP: Molecular biology

KW - inactive X chromosome

KW - TAD remodeling

KW - topological associated domains

KW - X chromosome inactivation

KW - XCI escape genes

KW - XCI maintenance

KW - Xist RNA

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DO - 10.1016/j.celrep.2025.115351

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SN - 2639-1856

VL - 44

JO - Cell Reports

JF - Cell Reports

IS - 3

M1 - 115351

ER -

B cell stimulation changes the structure and higher-order organization of the inactive X chromosome

Abstract

Keywords

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