grothlab.bsky.social
The Anja Groth group in Copenhagen studies chromatin replication, epigenetic memory and (epi)genome stability in the context of mitotic cell division
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Welcome Marcel!!
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Thank you, Tae-Kyeong!
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Together our work gives a molecular basis for histone supply regulation by CODANIN-1, read the full paper here: rdcu.be/ecbHq . Thanks to the Song lab at KAIST jijoonsong.bsky.social for taking us onboard as collaborators for this exciting new structure-function adventure!
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How important is CODANIN/ASF1A complex formation? Inhibiting dimerization in cells or introducing a pathogenic CDA-I mutation in the dimerization interface reduced ASF1A cytoplasmic sequestration. This shows the significance of CODANIN/ASF1A complex formation and possible disease relevance
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Which CODANIN binding sites are required for ASF1 regulation? Using inducible complementation of CODANIN-1 in cells, we found that mutation of both BD-N and HMH-C is needed to prevent cytoplasmic sequestration of ASF1A. Thus, CODANIN-1 regulates ASF1A nuclear import by this dual-binding mechanism.
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By binding in this way, CODANIN-1 occludes the two major histone-binding surfaces of ASF1A, preventing its chaperone activity. Interestingly, CODANIN-1 could also bind preformed ASF1A/H3-H4 using its B domains, suggesting that it may regulate ASF1 at multiple points in the histone supply chain.
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So, how does CODANIN-1 bind ASF1? Our cryo-EM structure reveals that CODANIN-1 forms a dimer, with each monomer binding two ASF1A molecules. These two ASF1As are held in proximal and distal positions by CODANINโs N-terminal B domain (BD-N) and C-terminal histone H3 mimic helix (HMH-C), respectively.
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A bit of background: ASF1 plays a central role in histone nuclear import and supply for replication & transcription. CODANIN-1 is commonly mutated in a rare form of heritable anaemia (CDA-I) and inhibits histone supply by ASF1. But we donโt currently understand these roles on the molecular level.
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Thank you, Jeroen!
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If youโre interested in epigenetic inheritance and cell division, check out the vacancies for 6 PhDs and Postdocs positions in our new Center for Epigenetic Cell Memory (EpiC): tinyurl.com/yvd93na2 6/n
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Want to dive deeper? ๐ง Read the full paper here: tinyurl.com/233y89d2 ๐๐. Last, a big thank you to all our collaborators and colleagues at #NNF-CPR ๐. #HistoneRecycling #Epigenetics #Chromatin #ScienceAdvances 5/n
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Our work highlights ๐ฉ๐๐ซ๐๐ง๐ญ๐๐ฅ ๐ก๐ข๐ฌ๐ญ๐จ๐ง๐ ๐ซ๐๐๐ฒ๐๐ฅ๐ข๐ง๐ ๐๐ฌ ๐ ๐ค๐๐ฒ ๐๐ฉ๐ข๐ ๐๐ง๐๐ญ๐ข๐ ๐ฌ๐๐๐๐ ๐ฎ๐๐ซ๐ โ histone modifications must be ๐๐๐๐ข๐๐ข๐๐ง๐ญ๐ฅ๐ฒ transmitted to ๐๐จ๐ญ๐ก daughter strands for this to work! Could failures in this process contribute to developmental disorders, cancer, or aging? More to explore! 4/n
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What happens next? Gene misregulation & differentiation defects start to emerge. But when ๐๐จ๐ญ๐ก leading & lagging strand recycling are disrupted (POLE4 & MCM2-2A), ๐ฌ๐จ๐ฆ๐ ๐ฉ๐๐ซ๐๐ง๐ญ๐๐ฅ ๐ก๐ข๐ฌ๐ญ๐จ๐ง๐๐ฌ ๐๐ซ๐ ๐ฅ๐จ๐ฌ๐ญ ๐ข๐ง ๐ญ๐ซ๐๐ง๐ฌ๐ฆ๐ข๐ฌ๐ฌ๐ข๐จ๐ง โworsening the defects. Unlike single mutants, cells now start to die! 3/n
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We use a degron to deplete POLE4, a leading strand recycler, in WT or a background defective in lagging strand recycling (MCM2-2A). The first epigenome alteration upon acute loss of leading strand recycling is ๐๐๐๐ฎ๐ฆ๐ฎ๐ฅ๐๐ญ๐ข๐จ๐ง ๐จ๐ ๐๐๐๐๐๐ฆ๐๐ - ๐ฐ๐ข๐ญ๐ก๐ข๐ง ๐-๐ ๐๐๐ฅ๐ฅ ๐๐ฒ๐๐ฅ๐๐ฌ - ๐๐๐๐จ๐ซ๐ ๐ญ๐ซ๐๐ง๐ฌ๐๐ซ๐ข๐ฉ๐ญ๐ข๐จ๐ง๐๐ฅ ๐๐ก๐๐ง๐ ๐๐ฌ! 2/n
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During replication, modified parental histones are transmitted to the daughter DNA strands - they are recycled. Recycled histones serve as agents of memory to maintain the epigenome in daughter cells! What happens when recycling is acutely disrupted? 1/n
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6 PhD and postdoc positions in the new Center for Epigenetic Cell Memory in Copenhagen, Denmark. Interested in epigenetics and chromatin b
biology? Consider applying here: tinyurl.com/yvd93na2.
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