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Sergeev, Mikhail

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Sergeev

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Mikhail

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Sergeev, Mikhail

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2014 - 20152

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Author's Publications: search.filters.isAuthorOfPublication.7470ab02-f92d-4d09-b4cf-c0f631ebf248

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    The quantitative architecture of centromeric chromatin
    (eLife Sciences Publications, Ltd, 2014) Bodor, Dani L; Mata, João F; Sergeev, Mikhail; David, Ana Filipa; Salimian, Kevan J; Panchenko, Tanya; Cleveland, Don W; Black, Ben E; Shah, Jagesh; Jansen, Lars ET
    The centromere, responsible for chromosome segregation during mitosis, is epigenetically defined by CENP-A containing chromatin. The amount of centromeric CENP-A has direct implications for both the architecture and epigenetic inheritance of centromeres. Using complementary strategies, we determined that typical human centromeres contain ∼400 molecules of CENP-A, which is controlled by a mass-action mechanism. This number, despite representing only ∼4% of all centromeric nucleosomes, forms a ∼50-fold enrichment to the overall genome. In addition, although pre-assembled CENP-A is randomly segregated during cell division, this amount of CENP-A is sufficient to prevent stochastic loss of centromere function and identity. Finally, we produced a statistical map of CENP-A occupancy at a human neocentromere and identified nucleosome positions that feature CENP-A in a majority of cells. In summary, we present a quantitative view of the centromere that provides a mechanistic framework for both robust epigenetic inheritance of centromeres and the paucity of neocentromere formation. DOI: http://dx.doi.org/10.7554/eLife.02137.001
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    ANKS6 is the critical activator of NEK8 kinase in embryonic situs determination and organ patterning
    (2015) Czarnecki, Peter; Gabriel, George C.; Manning, Danielle K.; Sergeev, Mikhail; Lemke, Kristi; Klena, Nikolai T.; Liu, Xiaoqin; Chen, Yu; Li, You; San Agustin, Jovenal T.; Garnaas, Maija; Francis, Richard J.; Tobita, Kimimasa; Goessling, Wolfram; Pazour, Gregory J.; Lo, Cecilia W.; Beier, David R.; Shah, Jagesh
    The ciliary kinase NEK8 plays a critical role in situs determination and cystic kidney disease, yet its exact function remains unknown. In this study we identify ANKS6 as a target and activator of NEK8. ANKS6 requires NEK8 for localizing to the ciliary inversin compartment (IC) and activates NEK8 by binding to its kinase domain. Here we demonstrate the functional importance of this interaction through the analysis of two novel mouse mutations, Anks6Streaker and Nek8Roc. Both display heterotaxy, cardiopulmonary malformations and cystic kidneys, a syndrome also characteristic of mutations in Invs and Nphp3, the other known components of the IC. The Anks6Strkr mutation decreases ANKS6 interaction with NEK8, precluding NEK8 activation. The Nek8Roc mutation inactivates NEK8 kinase function while preserving ANKS6 localization to the IC. Together, these data reveal the crucial role of NEK8 kinase activation within the IC, promoting proper left-right patterning, cardiopulmonary development and renal morphogenesis.