Department of Clinical and Experimental Medicine, Linkoping University, SE-58185 Linkoping, Sweden.
Department of Cell and Molecular Biology, Karolinska Institute, SE-17177 Stockholm, Sweden.
Development. 2022 Mar 1;149(5). doi: 10.1242/dev.200076. Epub 2022 Mar 4.
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 most 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 and Tac2-Pax6 neurons. These findings indicate that many aspects of the hypothalamic gene regulatory flow can proceed without the key H3K27me3 epigenetic repressor mark, but points to a unique sensitivity of particular neuronal subtypes to a disrupted epigenomic landscape.
下丘脑表现出惊人的细胞多样性，主要是在胚胎发生过程中由几种信号通路的相互作用和一系列转录因子建立的。然而，表观遗传线索对下丘脑发育的贡献仍不清楚。我们在发育中的小鼠下丘脑突变了多梳抑制复合物 2 基因 Eed，导致 H3K27me3 的丢失，这是一种基本的表观遗传抑制标记。这触发了后部表达调节剂（例如 Hox 同源基因）的异位表达、细胞周期抑制剂的上调和增殖减少。令人惊讶的是，尽管有这些影响，单细胞转录组分析显示，Eed 突变体中仍产生大多数神经元亚型。然而，我们观察到谷氨酸能/GABA 能双阳性细胞增加，以及多巴胺、下丘脑分泌素和 Tac2-Pax6 神经元的丧失/减少。这些发现表明，下丘脑基因调控流的许多方面可以在没有关键的 H3K27me3 表观遗传抑制标记的情况下进行，但表明特定神经元亚型对破坏的表观基因组景观具有独特的敏感性。
