Characterization of a 5-formylcytosine chromocenter in Xenopus embryos
Final Report Abstract
In active DNA demethylation, TET enzymes oxidize 5‐methylcytosine to 5‐hydroxymethylcytosine, 5‐formylcytosine (5fC), and 5‐carboxylcytosine as demethylation intermediates. An outstanding question is whether these oxidized cytosine derivatives have functional roles beyond being demethylation intermediates. We had discovered a 5fC nuclear chromocenter, which transiently forms during zygotic genome activation (ZGA) in Xenopus embryos. The aim of the DFG‐funded project was to characterize this 5fC chromocenter. During the funding period, we identified this chromocenter as the perinucleolar compartment, a structure localized at the periphery of the nucleolus, which is associated with transcription by RNA polymerase III (Pol III). By genomic profiling, 5fC is highly enriched on Pol III target genes and 5fC peaks correlate with active Pol III gene expression. Via manipulating Tet and Tdg enzymes, we find that 5fC is required as regulatory mark to promote Pol III and TFIIIC recruitment and activation of Pol III target genes. The results indicate an unexpected role of 5fC as epigenetic regulator during Pol III gene expression in early vertebrate development.
Publications
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(2017). Angiopoietin‐like 4 is a Wnt Signaling Antagonist that Promotes LRP6 Turnover. Dev Cell. 43, 71‐82
Kirsch N, Chang LS, Koch S, Glinka A, Dolde C, Colozza G, Benitez MDJ, De Robertis EM, and Niehrs C
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(2018). Impaired DNA demethylation of C/EBP sites causes premature aging. Genes Dev. 32, 742‐762
Schäfer A, Mekker B, Mallick M, Vastolo V, Karaulanov E, Sebastian D, von der Lippen C, Epe B, Downes DJ, Scholz C, and Niehrs C
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(2019). GADD45 promotes locus‐specific DNA demethylation and 2C cycling in embryonic stem cells. Genes Dev. 33, 782‐798
Schüle KM, Leichsenring M, Andreani T, Vastolo V, Mallick M, Musheev MU, Karaulanov E, Niehrs C
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(2019). GADD45A binds R‐loops and recruits TET1 to CpG island promoters. Nat. Genet. 51, 217‐223
Arab K, Karaulanov E, Musheev M, Trnka P, Schäfer A., Grummt I, and Niehrs C
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(2019). NEIL1 and NEIL2 DNA glycosylases protect neural crest development against mitochondrial oxidative stress. eLIFE. 49044
Han D, Schomacher L, Schüle KM, Mallick M, Musheev MU, Karaulanov E, Krebs L, von Seggern A, Niehrs C
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(2020). Regulatory R‐loops as facilitators of gene expression and genome stability. Nat Rev Mol Cell Biol. 21, 167–178
Niehrs C and Luke B
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(2020). The origin of genomic N6‐methyl‐deoxyadenosine in mammalian cells. Nat. Chem Biol. 16,630‐634
Musheev MU, Baumgärtner A, Krebs L, Niehrs C
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(2020). The tumor suppressor PTPRK promotes ZNRF3 internalization and is required for Wnt inhibition in the Spemann organizer. eLIFE. 51248
Chang LS, Kim M, Glinka A, Reinhard C, Niehrs C
