scholarly journals Megadomains and superloops form dynamically but are dispensable for X-chromosome inactivation and gene escape

2018 ◽  
Author(s):  
John E. Froberg ◽  
Stefan F. Pinter ◽  
Andrea J. Kriz ◽  
Teddy Jégu ◽  
Jeannie T. Lee
Keyword(s):  
Gene Silencing ◽  
X Chromosome ◽  
Nuclear Localization ◽  
Functional Significance ◽  
Xist Expression ◽  
H3k27 Methylation ◽  
3D Genome ◽  
Inactive X Chromosome ◽  
Topologically Associated Domains ◽  
Escape From X Inactivation

ABSTRACTThe mammalian inactive X-chromosome (Xi) is structurally distinct from all other chromosomes and serves as a model for how the 3D genome is organized. The Xi shows weakened topologically associated domains and is instead organized into megadomains and superloops directed by the noncoding loci, Dxz4 and Firre. Their functional significance is presently unclear, though one study suggests that they permit Xi genes to escape silencing. Here, we find that megadomains do not precede Xist expression or Xi gene silencing. Deleting Dxz4 disrupts megadomain formation, whereas deleting Firre weakens intra-megadomain interactions. Surprisingly, however, deleting Dxz4 and Firre has no impact on Xi silencing and gene escape. Nor does it affect Xi nuclear localization, stability, or H3K27 methylation. Additionally, ectopic integration of Dxz4 and Xist is not sufficient to form megadomains on autosomes, further uncoupling megadomain formation from chromosomal silencing. We conclude that Dxz4 and megadomains are dispensable for Xi silencing and escape from X-inactivation.

scholarly journals When the Lyon(ized chromosome) roars: ongoing expression from an inactive X chromosome

2017 ◽  
Vol 372 (1733) ◽  
pp. 20160355 ◽  
Author(s):  
Laura Carrel ◽  
Carolyn J. Brown
Keyword(s):  
X Chromosome ◽  
X Chromosome Inactivation ◽  
X Inactivation ◽  
Chromosome Inactivation ◽  
Sequencing Technologies ◽  
Inactive X Chromosome ◽  
Underlying Basis ◽  
Inactivation Process ◽  
Escape From X Inactivation ◽  
Mary Lyon

A tribute to Mary Lyon was held in October 2016. Many remarked about Lyon's foresight regarding many intricacies of the X-chromosome inactivation process. One such example is that a year after her original 1961 hypothesis she proposed that genes with Y homologues should escape from X inactivation to achieve dosage compensation between males and females. Fifty-five years later we have learned many details about these escapees that we attempt to summarize in this review, with a particular focus on recent findings. We now know that escapees are not rare, particularly on the human X, and that most lack functionally equivalent Y homologues, leading to their increasingly recognized role in sexually dimorphic traits. Newer sequencing technologies have expanded profiling of primary tissues that will better enable connections to sex-biased disorders as well as provide additional insights into the X-inactivation process. Chromosome organization, nuclear location and chromatin environments distinguish escapees from other X-inactivated genes. Nevertheless, several big questions remain, including what dictates their distinct epigenetic environment, the underlying basis of species differences in escapee regulation, how different classes of escapees are distinguished, and the roles that local sequences and chromosome ultrastructure play in escapee regulation. This article is part of the themed issue ‘X-chromosome inactivation: a tribute to Mary Lyon’.

scholarly journals Screen for reactivation of MeCP2 on the inactive X chromosome identifies the BMP/TGF-β superfamily as a regulator of XIST expression

2017 ◽  
Vol 114 (7) ◽  
pp. 1619-1624 ◽  
Author(s):  
Smitha Sripathy ◽  
Vid Leko ◽  
Robin L. Adrianse ◽  
Taylor Loe ◽  
Eric J. Foss ◽  
...  
Keyword(s):  
X Chromosome ◽  
Es Cells ◽  
X Chromosome Inactivation ◽  
Chromosome Inactivation ◽  
Xist Expression ◽  
Gene Encoding ◽  
Differentiated Cells ◽  
Inactive X Chromosome ◽  
Morphogenetic Protein ◽  
Therapeutic Opportunity

Rett syndrome (RS) is a debilitating neurological disorder affecting mostly girls with heterozygous mutations in the gene encoding the methyl-CpG–binding protein MeCP2 on the X chromosome. Because restoration of MeCP2 expression in a mouse model reverses neurologic deficits in adult animals, reactivation of the wild-type copy of MeCP2 on the inactive X chromosome (Xi) presents a therapeutic opportunity in RS. To identify genes involved in MeCP2 silencing, we screened a library of 60,000 shRNAs using a cell line with a MeCP2 reporter on the Xi and found 30 genes clustered in seven functional groups. More than half encoded proteins with known enzymatic activity, and six were members of the bone morphogenetic protein (BMP)/TGF-β pathway. shRNAs directed against each of these six genes down-regulated X-inactive specific transcript (XIST), a key player in X-chromosome inactivation that encodes an RNA that coats the silent X chromosome, and modulation of regulators of this pathway both in cell culture and in mice demonstrated robust regulation of XIST. Moreover, we show that Rnf12, an X-encoded ubiquitin ligase important for initiation of X-chromosome inactivation and XIST transcription in ES cells, also plays a role in maintenance of the inactive state through regulation of BMP/TGF-β signaling. Our results identify pharmacologically suitable targets for reactivation of MeCP2 on the Xi and a genetic circuitry that maintains XIST expression and X-chromosome inactivation in differentiated cells.

scholarly journals The non-canonical SMC protein SmcHD1 antagonises TAD formation on the inactive X chromosome

2018 ◽  
Author(s):  
Michal R Gdula ◽  
Tatyana B Nesterova ◽  
Greta Pintacuda ◽  
Jonathan Godwin ◽  
Ye Zhan ◽  
...  
Keyword(s):  
X Chromosome ◽  
Gene Activation ◽  
Higher Order ◽  
Partial Restoration ◽  
Chromosome Architecture ◽  
Inactive X Chromosome ◽  
Key Factor ◽  
Topologically Associated Domains ◽  
Unique Chromosome ◽  
Cpg Hypermethylation

AbstractThe inactive X chromosome (Xi) in female mammals adopts an atypical higher-order chromatin structure, manifested as a global loss of local topologically associated domains (TADs), and formation of two mega-domains. In this study we demonstrate that the non-canonical SMC family protein, SmcHD1, which is important for gene silencing on Xi, contributes to this unique chromosome architecture. Specifically, allelic mapping of the transcriptome and epigenome in SmcHD1 null cells revealed the appearance of sub-megabase domains defined by gene activation, CpG hypermethylation and depletion of Polycomb-mediated H3K27me3. These domains, which correlate with sites of SmcHD1 enrichment on Xi in wild-type cells, additionally adopt features of active X chromosome higher-order chromosome architecture, including partial restoration of TAD boundaries. Xi chromosome architecture changes also occurred in an acute SmcHD1 knockout model, but in this case, independent of Xi gene de-repression. We conclude that SmcHD1 is a key factor in antagonising TAD formation on Xi.

scholarly journals H4K20me1 and H3K27me3 are concurrently loaded onto the inactive X chromosome but dispensable for inducing gene silencing

EMBO Reports ◽  
2021 ◽  
Author(s):  
Sjoerd J D Tjalsma ◽  
Mayako Hori ◽  
Yuko Sato ◽  
Aurelie Bousard ◽  
Akito Ohi ◽  
...  
Keyword(s):  
Gene Silencing ◽  
X Chromosome ◽  
Inactive X Chromosome

Inhibition of Atm and/or Atr disrupts gene silencing on the inactive X chromosome

2005 ◽  
Vol 337 (3) ◽  
pp. 875-880 ◽  
Author(s):  
Yan Ouyang ◽  
Jennifer Salstrom ◽  
Silvia Diaz-Perez ◽  
Shareef Nahas ◽  
Youko Matsuno ◽  
...  
Keyword(s):  
Gene Silencing ◽  
X Chromosome ◽  
Inactive X Chromosome

Uncoupling of X-linked gene silencing from XIST binding by DICER1 and chromatin modulation on human inactive X chromosome

Chromosoma ◽  
2014 ◽  
Vol 124 (2) ◽  
pp. 249-262 ◽  
Author(s):  
Satya Keerthi Kota ◽  
Debabani Roy Chowdhury ◽  
Lakshmi K. Rao ◽  
Venkata Padmalatha ◽  
Lalji Singh ◽  
...  
Keyword(s):  
Gene Silencing ◽  
X Chromosome ◽  
Linked Gene ◽  
Inactive X Chromosome

scholarly journals An Xist-dependent protein assembly mediates Xist localization and gene silencing

2020 ◽  
Author(s):  
Amy Pandya-Jones ◽  
Yolanda Markaki ◽  
Jacques Serizay ◽  
Tsotne Chitiashvilli ◽  
Walter Mancia ◽  
...  
Keyword(s):  
Gene Silencing ◽  
X Chromosome ◽  
Binding Proteins ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Repeat Sequence ◽  
Inactive X Chromosome ◽  
Dependent Protein ◽  
Self Association ◽  
Molecular Forces

SummaryNuclear compartments play diverse roles in regulating gene expression, yet the molecular forces and components driving compartment formation are not well understood. Studying how the lncRNA Xist establishes the inactive-X-chromosome (Xi)-compartment, we found that the Xist RNA-binding-proteins PTBP1, MATR3, TDP43, and CELF1 form a condensate to create an Xi-domain that can be sustained in the absence of Xist. The E-repeat-sequence of Xist serves a multivalent binding-platform for these proteins. Without the E-repeat, Xist initially coats the X-chromosome during XCI onset but subsequently disperses across the nucleus with loss of gene silencing. Recruitment of PTBP1, MATR3, TDP-43 or CELF1 to ΔE-Xist rescues these phenotypes, and requires both self-association of MATR3 and TDP-43 and a heterotypic PTBP1-MATR3-interaction. Together, our data reveal that Xist sequesters itself within the Xi-territory and perpetuates gene silencing by seeding a protein-condensate. Our findings uncover an unanticipated mechanism for epigenetic memory and elucidate the interplay between RNA and RNA-binding-proteins in creating compartments for gene regulation.

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