Non-catalytic role for MLL2 in controlling chromatin organisation and mobility during priming of pluripotent cells for differentiation

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Abstract How the chromatin regulator MLL2 (KMT2B) influences cell differentiation remains poorly understood. MLL2 is the main histone 3 lysine 4 (H3K4) trimethyltransferase acting at bivalent promoters in embryonic stem cells (ESCs) and is required for ESCs to differentiate into neuroectoderm. We show here that this requirement occurs during exit from naïve pluripotency, days before neuroectoderm differentiation is impaired. Although MLL2 knockout has only a subtle effect on transcription during exit, reducing the expression of a few important neuroectodermal transcription factors, it substantially remodels chromatin architecture, disrupting 3D chromatin loops associated with bivalent promoters. The enzymatic activity of MLL2 is not needed for stabilising these loops or for neuroectoderm differentiation. This non-catalytic function of MLL2 in stabilising 3D chromatin loops has implications for lineage specification. Because MLL2 shares features with all four MLLs, chromatin tethering, rather than H3K4 methylation, may represent the primary function of MLL proteins during lineage commitment.

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