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Selective Requirement for Polycomb Repressor Complex 2 in the Generation of Specific Hypothalamic Neuronal Sub-types

By Stefan Thor, Behzad Yaghmaeian Salmani, Brad Balderson, Susanne Bauer, Helen Ekman, Annika Starkenberg, Thomas Perlmann, Michael Piper, Mikael Boden

Posted 28 Jul 2021
bioRxiv DOI: 10.1101/2021.07.28.454060

The hypothalamus displays staggering cellular diversity, chiefly established during embryogenesis by the interplay of several signalling pathways and a battery of transcription factors. However, the contribution of epigenetic cues to hypothalamus development remains unclear. We mutated the Polycomb Repressor Complex 2 gene Eed in the developing mouse hypothalamus, which resulted in the loss of H3K27me3; a fundamental epigenetic repressor mark. This triggered ectopic expression of posteriorly expressed regulators (e.g., Hox homeotic genes), upregulation of cell cycle inhibitors and reduced proliferation. Surprisingly, despite these effects, single cell transcriptomic analysis revealed that the majority of neuronal subtypes were still generated in Eed mutants. However, we observed an increase in Glutamatergic/GABAergic double-positive cells, as well as loss/reduction of dopamine, Hypocretin/Orexin and Tac2 neurons. These findings indicate that many aspects of the hypothalamic gene regulatory flow can proceed without the key H3K27me3 epigenetic repressor mark, and points to a unique sensitivity of particular neuronal sub-types to a disrupted epigenomic landscape.

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