Reactivation of the inactive X chromosome in development and reprogramming

Ohhata, Tatsuya; Wutz, Anton

doi:10.1007/s00018-012-1174-3

Cited by 65 publications

(63 citation statements)

References 156 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The cellular mosaicism resulting from the analysis of the XCIP in females has long been used as a marker to investigate clonal development and relationship among distinct cell compartments in different human hematopoietic disorders 19,49,50 ; thus, a polyclonal XCIP in the absence of other genotypic markers (ie, KIT D816V) could be interpreted as an accumulation of otherwise reactive, nonclonal MCs. The apparent discrepancy observed between the genotypic clonality defined by the KIT D816V mutation and the polyclonal XCIP could be explained either by a hypothetical reactivation of the inactive X-chromosome 51 at any stage after the occurrence of the mutation in a committed HPC, or by the emergence of the KIT mutation in an uncommitted precursor/stem cell at relatively early stages of development (ie, embryogenesis), prior to the inactivation of the X-chromosome during hematopoiesis. Because in human somatic cells XCIP appears to be rather stable, 52 the second hypothesis seems most feasible.…”

Section: Discussionmentioning

confidence: 99%

KIT D816V–mutated bone marrow mesenchymal stem cells in indolent systemic mastocytosis are associated with disease progression

Garcia-Montero¹,

Jara‐Acevedo

Álvarez‐Twose

et al. 2016

Blood

View full text Add to dashboard Cite

Key Points• Acquisition of the KIT D816V mutation in an early pluripotent progenitor cell confers ISM cases a greater risk for disease progression.• Despite the early acquisition of the KIT mutation, onset of clinical symptoms of ISM is often delayed to middle adulthood.Multilineage involvement of bone marrow (BM) hematopoiesis by the somatic KIT D816V mutation is present in a subset of adult indolent systemic mastocytosis (ISM) patients in association with a poorer prognosis. Here, we investigated the potential involvement of BM mesenchymal stem cells (MSCs) from ISM patients by the KIT D816V mutation and its potential impact on disease progression and outcome. This mutation was investigated in highly purified BM MSCs and other BM cell populations from 83 ISM patients followed for a median of 116 months. KIT D816V-mutated MSCs were detected in 22 of 83 cases. All MSCmutated patients had multilineage KIT mutation (100% vs 30%, P 5 .0001) and they more frequently showed involvement of lymphoid plus myeloid BM cells (59% vs 22%; P 5 .03) and a polyclonal pattern of inactivation of the X-chromosome of KIT-mutated BM mast cells (64% vs 0%; P 5 .01) vs other multilineage ISM cases. Moreover, presence of KIT-mutated MSCs was associated with more advanced disease features, a greater rate of disease progression (50% vs 17%; P 5 .04), and a shorter progression-free survival (P £ .003). Overall, these results support the notion that ISM patients with mutated MSCs may have acquired the KIT mutation in a common pluripotent progenitor cell, prior to differentiation into MSCs and hematopoietic precursor cells, before the X-chromosome inactivation process occurs. From a clinical point of view, acquisition of the KIT mutation in an earlier BM precursor cell confers a significantly greater risk for disease progression and a poorer outcome. (Blood. 2016;127(6):761-768)

show abstract

Section: Discussionmentioning

confidence: 99%

KIT D816V–mutated bone marrow mesenchymal stem cells in indolent systemic mastocytosis are associated with disease progression

Garcia-Montero¹,

Jara‐Acevedo

Álvarez‐Twose

et al. 2016

Blood

View full text Add to dashboard Cite

show abstract

“…At the same time, the broad changes in replication timing and chromatin marks are both consistent with a transition to constitutive heterochromatin, suggesting that DXZ4 strongly influences the chromatin environment on the Xi chromosome. Given the influence of H3K9me3 on the reprogramming of somatic cells to pluripotency (32), it is conceivable that DXZ4 may facilitate that process during X chromosome reactivation (33)(34)(35).…”

Section: Discussionmentioning

confidence: 99%

Deletion of DXZ4 on the human inactive X chromosome alters higher-order genome architecture

Darrow

Huntley

Dudchenko

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

262

313

View full text Add to dashboard Cite

During interphase, the inactive X chromosome (Xi) is largely transcriptionally silent and adopts an unusual 3D configuration known as the "Barr body." Despite the importance of X chromosome inactivation, little is known about this 3D conformation. We recently showed that in humans the Xi chromosome exhibits three structural features, two of which are not shared by other chromosomes. First, like the chromosomes of many species, Xi forms compartments. Second, Xi is partitioned into two huge intervals, called "superdomains," such that pairs of loci in the same superdomain tend to colocalize. The boundary between the superdomains lies near DXZ4, a macrosatellite repeat whose Xi allele extensively binds the protein CCCTC-binding factor. Third, Xi exhibits extremely large loops, up to 77 megabases long, called "superloops." DXZ4 lies at the anchor of several superloops. Here, we combine 3D mapping, microscopy, and genome editing to study the structure of Xi, focusing on the role of DXZ4. We show that superloops and superdomains are conserved across eutherian mammals. By analyzing ligation events involving three or more loci, we demonstrate that DXZ4 and other superloop anchors tend to colocate simultaneously. Finally, we show that deleting DXZ4 on Xi leads to the disappearance of superdomains and superloops, changes in compartmentalization patterns, and changes in the distribution of chromatin marks. Thus, DXZ4 is essential for proper Xi packaging.

show abstract

“…In contrast, these two stem cell types show different epigenetic states of X chromosomes; XCR occurs in ESCs, whereas XCI occurs in EpiSCs. Thus, reactivation of X chromosomes is used as an indicator of naïve-state PSCs (Ohhata and Wutz, 2013;Pasque and Plath, 2015). However, currently there is no means of monitoring XCR in living cells.…”

Section: Introductionmentioning

confidence: 99%

Live imaging of X chromosome reactivation dynamics in early mouse development can discriminate naïve from primed pluripotent stem cells

et al. 2016

View full text Add to dashboard Cite

Pluripotent stem cells can be classified into two distinct states, naïve and primed, which show different degrees of potency. One difficulty in stem cell research is the inability to distinguish these states in live cells. Studies on female mice have shown that reactivation of inactive X chromosomes occurs in the naïve state, while one of the X chromosomes is inactivated in the primed state. Therefore, we aimed to distinguish the two states by monitoring X chromosome reactivation. Thus far, X chromosome reactivation has been analysed using fixed cells; here, we inserted different fluorescent reporter gene cassettes (mCherry and eGFP) into each X chromosome. Using these knock-in 'Momiji' mice, we detected X chromosome reactivation accurately in live embryos, and confirmed that the pluripotent states of embryos were stable ex vivo, as represented by embryonic and epiblast stem cells in terms of X chromosome reactivation. Thus, Momiji mice provide a simple and accurate method for identifying stem cell status based on X chromosome reactivation.

show abstract

Reactivation of the inactive X chromosome in development and reprogramming

Cited by 65 publications

References 156 publications

KIT D816V–mutated bone marrow mesenchymal stem cells in indolent systemic mastocytosis are associated with disease progression

KIT D816V–mutated bone marrow mesenchymal stem cells in indolent systemic mastocytosis are associated with disease progression

Deletion of DXZ4 on the human inactive X chromosome alters higher-order genome architecture

Live imaging of X chromosome reactivation dynamics in early mouse development can discriminate naïve from primed pluripotent stem cells

Contact Info

Product

Resources

About