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Biomedical subjects

Philippe Clerc

Publications and source records attributed to Philippe Clerc.

7 recordsLinked to original sources
PubMed2006

Random X-chromosome inactivation: skewing lessons for mice and men.

The mammalian X-chromosome exists in two flavors, active and inactive, in each cell of the adult female. This phenomenon originates from the process of random choice occurring early in development in a small number of progenitor cells in which the decision is made to inactivate either one or the other X chromosome on a cell-autonomous basis. Once made, this initial decision is irreversible, although exceptions exist in specific chromosomal territories and cell lineages. Recent findings implicate various factors, including non-coding RNAs and chromatin modification complexes, as effectors in the initiation and maintenance of X-chromosome inactivation. The functional redundancy of such factors almost certainly plays an important role in the stability of the inactive X. Studying skewing or bias opens an important opportunity for understanding facets of the random choice process.

Animals↗
PubMed2006

An essential role for the DXPas34 tandem repeat and Tsix transcription in the counting process of X chromosome inactivation.

A counting process senses the X chromosome/autosome ratio and ensures that X chromosome inactivation (XCI) initiates in the early female (XX) embryo and in differentiating female ES cells but not in their male (XY) counterparts. Counting depends on the X inactivation center (Xic), which contains the Xist gene encoding a nuclear RNA, which coats the inactive X chromosome and induces gene silencing. A 37-kb sequence lying 3' to the Xist gene is known to prevent initiation of XCI in male differentiating ES cells. This region contains the major and minor promoters of the Tsix gene, which runs antisense to Xist, and the DXPas34 tandem repeat lying close to the Tsix major promoter. We have addressed the role of these elements in counting by using male ES cells. Targeted deletion of DXPas34 impaired recruitment of RNA-polymerase II and TFIIB at the Tsix major promoter, resulting in low levels of Tsix expression in ES cells and moderate ectopic initiation of XCI upon differentiation. A deletion extending 3' to Xist and including the Tsix major promoter resulted in almost complete impairment of Tsix transcription and in efficient ectopic XCI upon differentiation of male ES cells. Internal deletions within the Tsix gene did not affect significantly the level of antisense transcription within Xist and had only minor effects upon differentiation. Our results identify a function for DXPas34 in murine XCI and demonstrate the critical role of Tsix transcription in preventing XCI in differentiating male ES cells and in normal functioning of the counting pathway.

Animals↗
PubMed2006

Transient colocalization of X-inactivation centres accompanies the initiation of X inactivation.

The initial differential treatment of the two X chromosomes during X-chromosome inactivation is controlled by the X-inactivation centre (Xic). This locus determines how many X chromosomes are present in a cell ('counting') and which X chromosome will be inactivated in female cells ('choice'). Critical control sequences in the Xic include the non-coding RNAs Xist and Tsix, and long-range chromatin elements. However, little is known about the process that ensures that X inactivation is triggered appropriately when more than one Xic is present in a cell. Using three-dimensional fluorescence in situ hybridization (FISH) analysis, we showed that the two Xics transiently colocalize, just before X inactivation, in differentiating female embryonic stem cells. Using Xic transgenes capable of imprinted but not random X inactivation, and Xic deletions that disrupt random X inactivation, we demonstrated that Xic colocalization is linked to Xic function in random X inactivation. Both long-range sequences and the Tsix element, which generates the antisense transcript to Xist, are required for the transient interaction of Xics. We propose that transient colocalization of Xics may be necessary for a cell to determine Xic number and to ensure the correct initiation of X inactivation.

Animals↗
PubMed2005

Functional assessment of mitral regurgitation by transthoracic echocardiography using standardized imaging planes diagnostic accuracy and outcome implications.

OBJECTIVES: We sought to assess the value of transthoracic echocardiography (TTE) using standardized imaging planes for the functional analysis of mitral regurgitation (MR) as well as for postoperative outcome implications. BACKGROUND: The feasibility of mitral valve repair is based on functional assessment of MR, mainly by transesophageal echocardiography (TEE). Considering the recent advances in TTE imaging, the incremental value of TEE in this setting needs to be re-examined. METHODS: Consecutive patients (n = 279; 181 men; median age 68 years [quartiles, 61 to 74]) who underwent surgery for MR were enrolled prospectively in two tertiary care centers. The accuracy of TTE (harmonic imaging) versus TEE for functional assessment of MR was evaluated against surgical findings. RESULTS: Valve repair (n = 237 patients, 85%) or replacement (n = 42) was predicted accurately by TTE in 97% of cases; TEE added significant information for only two patients. In the subgroup of degenerative MR (n = 190), agreement with surgical findings for the localization of prolapsed segments was 91% for TTE (kappa, 0.81) and 93% for TEE (kappa, 0.85) without incremental value of TEE (p = 0.40). Patients with single prolapse of the middle posterior scallop (P2) had a better postoperative outcome as compared with patients who had non-P2 lesions (p = 0.008). Furthermore, mitral replacement predicted by TTE was an independent predictor for postoperative long-term mortality (odds ratio 5.7, 95% confidence interval 1.97 to 16.4, p = 0.001). CONCLUSIONS: In experienced hands, functional assessment of MR by TTE can predict accurately valve repairability and has a strong influence on postoperative outcome. Thus, in most cases preoperative TEE is not mandatory, provided intraoperative TEE is performed.

Aged↗
PubMed2004

The region 3' to Xist mediates X chromosome counting and H3 Lys-4 dimethylation within the Xist gene.

A counting process senses the X chromosome/autosome ratio and ensures that X chromosome inactivation (XCI) initiates in the female (XX) but not in the male (XY) mouse embryo. Counting is regulated by the X-inactivation centre, which contains the Xist gene. Deleting 65 kb 3' to Xist in XO embryonic stem (ES) cells affects counting and results in inappropriate XCI upon differentiation. We show here that normal counting can be rescued in these deleted ES cells using cre/loxP re-insertion, and refine the location of elements controlling counting within a 20 kb bipartite domain. Furthermore, we show that the 65 kb deletion also leads to inappropriate XCI in XY differentiated ES cells, which excludes the involvement of sex-specific mechanisms in the initiation of XCI. At the chromatin level, we have found that the Xist gene corresponds to a peak of H3 Lys-4 dimethylation, which is dramatically and specifically affected by the deletion 3' to Xist. Our results raise the possibility that H3 Lys-4 dimethylation within Xist may be functionally implicated in the counting process.

3' Flanking Region↗
PubMed2003

Multiple elements within the Xic regulate random X inactivation in mice.

In female mammals, the majority of the genes on one of the two X-chromosomes are silenced by a process referred to as X-chromosome inactivation. The X-inactivation center (Xic), a complex genomic region on the X-chromosome which controls this process, contains the Xist gene encoding an untranslated RNA which plays a central role in the establishment of the transcriptional repression. The Xic encrypts a sophisticated program which coordinates X inactivation with sex and embryonic development. The present article reviews our current knowledge of the regulatory elements lying within the mouse Xic and of the mechanisms underlying random X inactivation.

Animals↗