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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

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

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

First, MORC2 ATPase mutations cause severe developmental disorders: we explain how ATPase activity is coupled to chromatin binding and CpG methylation patterning of different targets. That many of the hyperrepressed genes encode KRAB-ZNFs, themselves TE silencers, is conceptually fascinating! 7/X

Second, the factor directing human L1 methylation in early development was unknown - a deletion in the ancestral promoter is thought to evade silencing by the KRAB-ZNF/TRIM28 system. We show MORC2 is critical here, at least for those most dangerous elements transcribed in the pluripotent state. 8/X