KDM2A represses transcription of centromeric satellite repeats and maintains the heterochromatic state

Frescas, David; Guardavaccaro, Daniele; Kuchay, Shafi; Kato, Hiroyuki; Poleshko, Andrey; Basrur, Venkatesha; Elenitoba-Johnson, Kojo S.J.; Katz, Richard A.; Pagano, Michele

doi:10.4161/cc.7.22.7062

Cited by 129 publications

(147 citation statements)

References 42 publications

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“…Accumulation of RITS complex around the repeat region progressively leads the loss of its euchromatic character. Finally (3), in dimorphic adults, the repeat region becomes transcriptionally inactive, and heterochromatin is maybe locked by HP1 or related chromatin proteins such as KDM2A [59], or a second histone modification mark is missing [60]. Dicer and Argonaut are less abundant.…”

Section: Discussionmentioning

confidence: 99%

Chromatin structural changes around satellite repeats on the female sex chromosome in Schistosoma mansoni and their possible role in sex chromosome emergence

et al. 2012

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BackgroundIn the leuphotrochozoan parasitic platyhelminth Schistosoma mansoni, male individuals are homogametic (ZZ) whereas females are heterogametic (ZW). To elucidate the mechanisms that led to the emergence of sex chromosomes, we compared the genomic sequence and the chromatin structure of male and female individuals. As for many eukaryotes, the lower estimate for the repeat content is 40%, with an unknown proportion of domesticated repeats. We used massive sequencing to de novo assemble all repeats, and identify unambiguously Z-specific, W-specific and pseudoautosomal regions of the S. mansoni sex chromosomes.ResultsWe show that 70 to 90% of S. mansoni W and Z are pseudoautosomal. No female-specific gene could be identified. Instead, the W-specific region is composed almost entirely of 36 satellite repeat families, of which 33 were previously unknown. Transcription and chromatin status of female-specific repeats are stage-specific: for those repeats that are transcribed, transcription is restricted to the larval stages lacking sexual dimorphism. In contrast, in the sexually dimorphic adult stage of the life cycle, no transcription occurs. In addition, the euchromatic character of histone modifications around the W-specific repeats decreases during the life cycle. Recombination repression occurs in this region even if homologous sequences are present on both the Z and W chromosomes.ConclusionOur study provides for the first time evidence for the hypothesis that, at least in organisms with a ZW type of sex chromosomes, repeat-induced chromatin structure changes could indeed be the initial event in sex chromosome emergence.

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Section: Discussionmentioning

confidence: 99%

Chromatin structural changes around satellite repeats on the female sex chromosome in Schistosoma mansoni and their possible role in sex chromosome emergence

et al. 2012

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“…Through its Jumonji domain, KDM2A demethylates pericentric H3K36me2, thereby maintaining a closed chromatin state and silencing nascent transcription. KDM2A knockdown resulted in a loss of HP1 from the pericentromere and a large increase in major or alpha satellite transcripts in both mouse and human cells, respectively (Frescas et al 2008) (Fig. 2a).…”

Section: Centromeric Transcription In Cellular Stress and Diseasementioning

confidence: 99%

“…The tumor suppressor lysine-specific demethylase 2A (KDM2A) was identified as a heterochromatin associated protein that is downregulated in prostate cancer (Frescas et al 2008). Through its Jumonji domain, KDM2A demethylates pericentric H3K36me2, thereby maintaining a closed chromatin state and silencing nascent transcription.…”

Section: Centromeric Transcription In Cellular Stress and Diseasementioning

confidence: 99%

“…A few recent studies have addressed how and why centromeric transcription changes during oncogenesis (Frescas et al 2008;Iotti et al 2011;Slee et al 2012;Ting et al 2011;Zhu et al 2011). The tumor suppressor lysine-specific demethylase 2A (KDM2A) was identified as a heterochromatin associated protein that is downregulated in prostate cancer (Frescas et al 2008).…”

Section: Centromeric Transcription In Cellular Stress and Diseasementioning

confidence: 99%

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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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“…[28][29][30][31][32] Although both KDM2A-LF and KDM2A-SF are known to directly interact with HP1a, only KDM2A-LF has been studied with regards to regulation of pericentromeric heterochromatin. 33 Moreover, KDM2A-SF has been found to be overexpressed in cancer cells and to promote their proliferation most likely through its ability to induce rDNA transcription. 23,24 In this study, we characterize KDM2A-SF more in detail and we show that KDM2A-SF, unlike its full length canonical KDM2A-LF counterpart, forms distinct nuclear heterochromatic bodies in an HP1a-dependent manner.…”

Section: Introductionmentioning

confidence: 99%

A demethylation deficient isoform of the lysine demethylase KDM2A interacts with pericentromeric heterochromatin in an HP1a-dependent manner

Lađinović

Novotná

Jakšová

et al. 2017

Nucleus

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Histone modifications have a profound impact on the chromatin structure and gene expression and their correct establishment and recognition is essential for correct cell functioning. Malfunction of histone modifying proteins is associated with developmental defects and diseases and detailed characterization of these proteins is therefore very important. The lysine specific demethylase KDM2A is a CpG island binding protein that has been studied predominantly for its ability to regulate CpG island-associated gene promoters by demethylating their H3K36me2. However, very little attention has been paid to the alternative KDM2A isoform that lacks the N-terminal demethylation domain, KDM2A-SF. Here we characterized KDM2A-SF more in detail and we found that, unlike the canonical full length KDM2A-LF isoform, KDM2A-SF forms distinct nuclear heterochromatic bodies in an HP1a dependent manner. Our chromatin immunoprecipitation experiments further showed that KDM2A binds to transcriptionally silent pericentromeric regions that exhibit high levels of H3K36me2. H3K36me2 is the substrate of the KDM2A demethylation activity and the high levels of this histone modification in the KDM2A-bound pericentromeric regions imply that these regions are occupied by the demethylation deficient KDM2A-SF isoform.

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KDM2A represses transcription of centromeric satellite repeats and maintains the heterochromatic state

Cited by 129 publications

References 42 publications

Chromatin structural changes around satellite repeats on the female sex chromosome in Schistosoma mansoni and their possible role in sex chromosome emergence

Chromatin structural changes around satellite repeats on the female sex chromosome in Schistosoma mansoni and their possible role in sex chromosome emergence

Pericentric and centromeric transcription: a perfect balance required

A demethylation deficient isoform of the lysine demethylase KDM2A interacts with pericentromeric heterochromatin in an HP1a-dependent manner

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