Accumulation of small murine minor satellite transcripts leads to impaired centromeric architecture and function

Bouzinba-Ségard, Haniaa; Ferri, F.; Francastel, Claire

doi:10.1016/j.bcmd.2006.10.045

Cited by 68 publications

(96 citation statements)

References 22 publications

(35 reference statements)

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“…In addition, aberrant expression of meiosis-specific genes can lead to mitotic catastrophe (22). Along the same lines, we have shown in a previous work that deregulated transcription of centromeric minor satellite repeats, associated with their hypomethylation, could lead to aberrant chromosome segregation and aneuploidy (54). Thus, it appears that the potential contribution of aberrant transcription of centromeric repeats or meiotic genes, as a consequence of DNA hypomethylation to chromosome instability, represents a promising field of investigation.…”

Section: Discussionmentioning

confidence: 62%

Dnmt3b recruitment through E2F6 transcriptional repressor mediates germ-line gene silencing in murine somatic tissues

Velasco

Hubé

Rollin

et al. 2010

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

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121

122

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Methylation of cytosine residues within the CpG dinucleotide in mammalian cells is an important mediator of gene expression, genome stability, X-chromosome inactivation, genomic imprinting, chromatin structure, and embryonic development. The majority of CpG sites in mammalian cells is methylated in a nonrandom fashion, raising the question of how DNA methylation is distributed along the genome. Here, we focused on the functions of DNA methyltransferase-3b (Dnmt3b), of which deregulated activity is linked to several human pathologies. We generated Dnmt3b hypomorphic mutant mice with reduced catalytic activity, which first revealed a deregulation of Hox genes expression, consistent with the observed homeotic transformations of the posterior axis. In addition, analysis of deregulated expression programs in Dnmt3b mutant embryos, using DNA microarrays, highlighted illegitimate activation of several germ-line genes in somatic tissues that appeared to be linked directly to their hypomethylation in mutant embryos. We provide evidence that these genes are direct targets of Dnmt3b. Moreover, the recruitment of Dnmt3b to their proximal promoter is dependant on the binding of the E2F6 transcriptional repressor, which emerges as a common hallmark in the promoters of genes found to be up-regulated as a consequence of impaired Dnmt3b activity. Therefore, our results unraveled a coordinated regulation of genes involved in meiosis, through E2F6-dependant methylation and transcriptional silencing in somatic tissues.DNA methylation | immunodeficiency | centromeric instability | facial anomalies | E2F family | hypomorphic mutation | hox genes

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Section: Discussionmentioning

confidence: 62%

Dnmt3b recruitment through E2F6 transcriptional repressor mediates germ-line gene silencing in murine somatic tissues

Velasco

Hubé

Rollin

et al. 2010

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

Self Cite

121

122

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“…Centromeric chromatin is highly compacted and consists of transcriptionally repressed satellite repeats (44,45). HP1 has been shown to concentrate mainly at pericentromeric heterochromatin (30).…”

Section: Loss Of Orc Proteins Results In Abnormal Compaction Of Satelmentioning

confidence: 99%

Human origin recognition complex is essential for HP1 binding to chromatin and heterochromatin organization

Prasanth

Shen

Prasanth

et al. 2010

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

130

146

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The origin recognition complex (ORC) is a DNA replication initiator protein also known to be involved in diverse cellular functions including gene silencing, sister chromatid cohesion, telomere biology, heterochromatin localization, centromere and centrosome activity, and cytokinesis. We show that, in human cells, multiple ORC subunits associate with hetereochromatin protein 1 (HP1) α-and HP1β-containing heterochromatic foci. Fluorescent bleaching studies indicate that multiple subcomplexes of ORC exist at heterochromatin, with Orc1 stably associating with heterochromatin in G1 phase, whereas other ORC subunits have transient interactions throughout the cell-division cycle. Both Orc1 and Orc3 directly bind to HP1α, and two domains of Orc3, a coiled-coil domain and a mod-interacting region domain, can independently bind to HP1α; however, both are essential for in vivo localization of Orc3 to heterochromatic foci. Direct binding of both Orc1 and Orc3 to HP1 suggests that, after the degradation of Orc1 at the G1/S boundary, Orc3 facilitates assembly of ORC/HP1 proteins to chromatin. Although depletion of Orc2 and Orc3 subunits by siRNA caused loss of HP1α association to heterochromatin, loss of Orc1 and Orc5 caused aberrant HP1α distribution only to pericentric heterochromatin-surrounding nucleoli. Depletion of HP1α from human cells also shows loss of Orc2 binding to heterochromatin, suggesting that ORC and HP1 proteins are mutually required for each other to bind to heterochromatin. Similar to HP1α-depleted cells, Orc2 and Orc3 siRNA-treated cells also show loss of compaction at satellite repeats, suggesting that ORC together with HP1 proteins may be involved in organizing higherorder chromatin structure and centromere function.centromere | origin recognition complex | pericentric heterochromatin | chromatin structure

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“…In mouse cells stressed by chemical exposure, minor satellite transcription increases, resulting in an accumulation of 120nt transcripts (Bouzinba-Segard et al 2006). While unstressed cells were found to contain a basal level of these CTs, the forced accumulation of transcripts impaired centromere function, leading to decondensed centromeres and mitotic defects, such as multiple spindle attachments, loss of sister chromatid cohesion, and anueploidy (Bouzinba-Segard et al 2006). Notably, CenpB and CenpC were retained normally in these cells, implying that inner kinetochore function was perhaps unaffected.…”

Section: Centromeric Transcription In Cellular Stress and Diseasementioning

confidence: 99%

Pericentric and centromeric transcription: a perfect balance required

2012

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The pericentromere and centromere regions of the genome have previously been considered tightly compacted and transcriptionally inert. However, there is mounting evidence that these regions not only actively produce transcripts but that these pericentric and centromeric transcripts are also vital to maintaining genome stability and proper cell division. In this review, we define the pericentromere and centromere of eukaryotic chromosomes in terms of their histone modifications and their nascent transcripts. In addition, we present the currently known roles these transcripts play in heterochromatin formation, development, and differentiation, as well as their interaction with centromeric proteins, and ultimately centromere function. Recent work has added considerable complexity to the theoretical framework defining the innate requirement for pericentric and centromeric transcription. It is clear that maintaining a fine balance of transcriptional output is critical, as deviations from this balance result in centromere disfunction and genomic instability.

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Accumulation of small murine minor satellite transcripts leads to impaired centromeric architecture and function

Cited by 68 publications

References 22 publications

Dnmt3b recruitment through E2F6 transcriptional repressor mediates germ-line gene silencing in murine somatic tissues

Dnmt3b recruitment through E2F6 transcriptional repressor mediates germ-line gene silencing in murine somatic tissues

Human origin recognition complex is essential for HP1 binding to chromatin and heterochromatin organization

Pericentric and centromeric transcription: a perfect balance required

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