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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

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

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

Genetic loss of L1 silencing due to MORC2 mutation had severe consequences on cellular fitness in a 2D NPC model after pluripotency exit - rescued upon L1 CRISPRi! (shout out to @anitaada.bsky.social @jakobssonlab.bsky.social for the vector - see www.biorxiv.org/content/10.1... ) 5/X

Apart from relating human genetic L1 activation to a clear cellular phenotype in development cell models, we are excited about these results for two main reasons... 6/X