Position effect of translocations involving the inactive X chromosome: physical linkage to XIC/XIST does not lead to long-range de novo inactivation in human differentiated cells

Balanced X-autosome translocations are rare, and female carriers are a clinically heterogeneous group of patients, with phenotypically normal women, history of recurrent miscarriage, gonadal dysfunction, X-linked disorders or congenital abnormalities, and/or developmental delay. We investigated a patient with ade novoX;19 translocation. The six-year-old girl has been evaluated due to hyperactivity, social interaction impairment, stereotypic and repetitive use of language with echolalia, failure to follow parents/caretakers orders, inconsolable outbursts, and persistent preoccupation with parts of objects. The girl has normal cognitive function. Her measurements are within normal range, and no other abnormalities were found during physical, neurological, or dysmorphological examinations. Conventional cytogenetic analysis showed ade novobalanced translocation, with the karyotype 46,X,t(X;19)(p21.2;q13.4). Replication banding showed a clear preference for inactivation of the normal X chromosome. The translocation was confirmed by FISH and Spectral Karyotyping (SKY). Although abnormal phenotypes associated withde novobalanced chromosomal rearrangements may be the result of disruption of a gene at one of the breakpoints, submicroscopic deletion or duplication, or a position effect, X; autosomal translocations are associated with additional unique risk factors including X-linked disorders, functional autosomal monosomy, or functional X chromosome disomy resulting from the complex X-inactivation process.

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P X.11 Position effect of translocations involving the inactive X-chromosome. A study combining FISH and immunocyto-genetics

Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis ◽

10.1016/s0027-5107(97)82848-5 ◽

1997 ◽

Vol 379 (1) ◽

pp. S72-S73 ◽

Cited By ~ 1

Author(s):

J. Surralles ◽

A.T. Natarajan

Keyword(s):

X Chromosome ◽

Position Effect ◽

Inactive X Chromosome

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Orientation-dependent Dxz4 contacts shape the 3D structure of the inactive X chromosome

10.1101/165340 ◽

2017 ◽

Cited By ~ 4

Author(s):

G. Bonora ◽

X. Deng ◽

H. Fang ◽

V. Ramani ◽

R. Qui ◽

...

Keyword(s):

Long Range ◽

X Chromosome ◽

3D Structure ◽

Chromatin Accessibility ◽

Ctcf Binding ◽

Partial Restoration ◽

Multiple Loci ◽

Inactive X Chromosome ◽

Repeat Locus ◽

Contact Distribution

AbstractThe mammalian inactive X chromosome (Xi) condenses into a bipartite structure with two superdomains of frequent long-range contacts separated by a boundary or hinge region. Using in situ DNase Hi-C in mouse cells with deletions or inversions within the hinge we show that the conserved repeat locus Dxz4 alone is sufficient to maintain the bipartite structure and that Dxz4 orientation controls the distribution of long-range contacts on the Xi. Frequent long-range contacts between Dxz4 and the telomeric superdomain are either lost after its deletion or shifted to the centromeric superdomain after its inversion. This massive reversal in contact distribution is consistent with the reversal of CTCF motif orientation at Dxz4. De-condensation of the Xi after Dxz4 deletion is associated with partial restoration of TADs normally attenuated on the Xi. There is also an increase in chromatin accessibility and CTCF binding on the Xi after Dxz4 deletion or inversion, but few changes in gene expression, in accordance with multiple epigenetic mechanisms ensuring X silencing. We propose that Dxz4 represents a structural platform for frequent long-range contacts with multiple loci in a direction dictated by the orientation of a bank of CTCF motifs at Dxz4, which may work as a ratchet to form the distinctive bipartite structure of the condensed Xi.

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

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1621356114 ◽

2017 ◽

Vol 114 (7) ◽

pp. 1619-1624 ◽

Cited By ~ 24

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.

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A polyglutamine domain is required for de novo CIZ1 assembly formation at the inactive X chromosome

10.1101/2020.11.10.376558 ◽

2020 ◽

Author(s):

Sajad Sofi ◽

Louisa Williamson ◽

Gabrielle L. Turvey ◽

Charlotte Scoynes ◽

Claire Hirst ◽

...

Keyword(s):

X Chromosome ◽

Zinc Finger Protein ◽

De Novo ◽

Dependent Manner ◽

Inactive X Chromosome ◽

C Terminus ◽

Alternatively Spliced ◽

Polyglutamine Tract ◽

Alternatively Spliced Exons

SummaryCIP1-interacting zinc finger protein 1 (CIZ1) forms large assemblies at the inactive X chromosome (Xi) in female fibroblasts in an Xist lncRNA-dependent manner. Here we address the requirements for assembly formation, and show that CIZ1 interacts directly with Xist via two independent domains in its N- and C-terminus. Interaction with Xist repeat E, assembly at Xi in cells, and the complexity of self-assemblies formed in vitro, are all modulated by alternatively-spliced exons that include two glutamine-rich prion-like domains (PLD1 and PLD2), both conditionally excluded from the N-terminal domain. Exclusion of PLD1 alone is sufficient to abrogate de novo establishment of new CIZ1 assemblies and Xi territories enriched for H3K27me3 in CIZ1-null fibroblasts. Together the data suggest that PLD1-driven CIZ1 assemblies form at Xi, are nucleated by interaction with Xist and amplified by multivalent interaction with RNA, so implicating a polyglutamine tract in the maintenance of epigenetic state.

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Long-range chromatin interactions on the inactive X and at Hox clusters are regulated by the non-canonical SMC protein Smchd1

10.1101/342212 ◽

2018 ◽

Cited By ~ 2

Author(s):

Natasha Jansz ◽

Andrew Keniry ◽

Marie Trussart ◽

Heidi Bildsoe ◽

Tamara Beck ◽

...

Keyword(s):

Gene Regulation ◽

Long Range ◽

X Chromosome ◽

Chromatin Structure ◽

Short Range ◽

Higher Order ◽

Chromatin Interactions ◽

Inactive X Chromosome ◽

Hox Clusters

AbstractThe regulation of higher order chromatin structure is complex and dynamic; however we do not yet understand the full suite of mechanisms governing architecture. Here we reveal the non-canonical SMC protein Smchd1 as a novel regulator of long-range chromatin interactions, and add it to the canon of epigenetic proteins required for Hox gene regulation. The effect of losing Smchd1-dependent chromatin interactions has varying outcomes dependent on chromatin context. At autosomal targets transcriptionally sensitive to Smchd1 deletion, we find increased short-range interactions and ectopic enhancer activation. By contrast, the inactive X chromosome is transcriptionally refractive to Smchd1 ablation, despite chromosome-wide increases in short-range interactions. There we observe spreading of H3K27me3 domains into regions not normally decorated by this mark. Together these data suggest Smchd1 has the capacity to insulate the chromatin, thereby limiting access to other chromatin modifying proteins.

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Smchd1 regulates long-range chromatin interactions on the inactive X chromosome and at Hox clusters

Nature Structural & Molecular Biology ◽

10.1038/s41594-018-0111-z ◽

2018 ◽

Vol 25 (9) ◽

pp. 766-777 ◽

Cited By ~ 31

Author(s):

Natasha Jansz ◽

Andrew Keniry ◽

Marie Trussart ◽

Heidi Bildsoe ◽

Tamara Beck ◽

...

Keyword(s):

Long Range ◽

X Chromosome ◽

Chromatin Interactions ◽

Inactive X Chromosome ◽

Hox Clusters

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Deciphering the Role of the Barr Body in Malignancy: An insight into head and neck cancer

Sultan Qaboos University Medical Journal [SQUMJ] ◽

10.18295/squmj.2017.17.04.003 ◽

2018 ◽

Vol 17 (4) ◽

pp. 389 ◽

Cited By ~ 1

Author(s):

Deepti Sharma ◽

George Koshy ◽

Shruti Gupta ◽

Bhushan Sharma ◽

Sonal Grover

Keyword(s):

Head And Neck ◽

X Chromosome ◽

Expression Patterns ◽

Barr Body ◽

X Chromosomes ◽

Differentiated Cells ◽

Inactive X Chromosome ◽

Poorly Differentiated ◽

Differentiation Status

X chromosome inactivation is the epitome of epigenetic regulation and long non-coding ribonucleic acid function. The differentiation status of cells has been ascribed to X chromosome activity, with two active X chromosomes generally only observed in undifferentiated or poorly differentiated cells. Recently, several studies have indicated that the reactivation of an inactive X chromosome or X chromosome multiplication correlates with the development of malignancy; however, this concept is still controversial. This review sought to shed light on the role of the X chromosome in cancer development. In particular, there is a need for further exploration of the expression patterns of X-linked genes in cancer cells, especially those in head and neck squamous cell carcinoma (HNSCC), in order to identify different prognostic subpopulations with distinct clinical implications. This article proposes a functional relationship between the loss of the Barr body and the disproportional expression of X-linked genes in HNSCC development.

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