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Christopher Douse
@chdouse.bsky.social

Very proud of this work where we define how the MORC2 ATPase directs CpG methylation of active human L1 transposons in early development. Thanks to co-authors, funders & wonderful environment @lundstem.bsky.social www.biorxiv.org/content/10.1... Brief thread below (do people still do that?) 1/X

biorxiv.orgMORC2 directs transcription-dependent CpG methylation of human LINE-1 transposons in early neurodevelopmentMethylation of CpG dinucleotides is essential for silencing genomic repeats such as LINE-1 retrotransposons (L1s) in the germline and soma. Evolutionarily-young L1s are transcribed in human pluripoten...
Christopher Douse
@chdouse.bsky.social

We engineered mutations to figure out requirements of MORC2 binding to its distinct chromatin targets. Accumulation of MORC2 at L1s and other broad targets requires reversible ATP-dependent dimerization, whereas engagement of gene promoters does not. Mutation misdirects MORC2 onto promoters. 2/X

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Christopher Douse
@chdouse.bsky.social

Modelling these effects in pluripotent stem cells, we observed loss of function (transcriptional activation) at L1s and gain of function (transcriptional repression) at promoters, an effect which persisted upon differentiation to neural progenitors. 3/X

Christopher Douse
@chdouse.bsky.social

Explaining the persistence of these transcriptional phenotypes we found striking loss of CpG methylation over the youngest human- and hominoid specific L1s (including polymorphic alleles), and hypermethylation of gene promoters. 4/X