Spatial enhancer activation determines inhibitory neuron identity (ChIP-seq of MEIS transcription factors)

The mammalian telencephalon contains a tremendous diversity of GABAergic projection neuron and interneuron types, that originate in a germinal zone of the embryonic basal ganglia. How genetic information in this transient structure is transformed into different cell types is not yet fully understood. Using a combination of in vivo lineage tracing, CRISPR perturbation and ChIP-seq in mice, we found that the transcription factor MEIS2 favors the development of projection neurons through genomic binding sites in regulatory enhancers of projection neuron specific genes. MEIS2 requires the presence of the homeodomain transcription factor DLX5 to direct its functional activity towards these sites. In interneurons, the activation of projection neuron specific enhancers by MEIS2 and DLX5 is repressed by the transcription factor LHX6. When MEIS2 carries a mutation associated with intellectual disability in humans, it is less effective at activating enhancers involved in projection neuron development. This suggests that GABAergic differentiation may be impaired in patients carrying this mutation. Our research has uncovered a mechanism by which the selective activation of enhancers plays a crucial role in the establishment of neuronal identity, as well as in potential pathological mechanisms MEIS ChIP-seq of ganglionic eminences

哺乳动物端脑（telencephalon）包含种类极其丰富的γ-氨基丁酸能投射神经元（GABAergic projection neuron）与中间神经元（interneuron）亚型，所有此类神经元均起源于胚胎基底神经节的生发区。目前学界尚未完全阐明，该暂时性结构内的遗传信息如何分化为多种细胞类型。本研究结合小鼠体内谱系示踪（in vivo lineage tracing）、CRISPR基因扰动及染色质免疫共沉淀测序（ChIP-seq）技术开展实验，发现转录因子MEIS2可通过结合投射神经元特异性基因调控增强子中的基因组结合位点，促进投射神经元发育。MEIS2需依赖同源结构域转录因子DLX5，才能将其功能活性定向作用于上述结合位点。在中间神经元中，MEIS2与DLX5对投射神经元特异性增强子的激活过程会被转录因子LHX6抑制。当MEIS2携带与人类智力障碍相关的突变时，其激活投射神经元发育相关增强子的能力显著下降。这提示携带该突变的患者体内GABA能神经元的分化过程可能受损。本研究揭示了一种核心机制：增强子的选择性激活在神经元身份确立及潜在病理机制中发挥关键作用。本研究相关实验数据集包含基于神经节隆起（ganglionic eminences）的MEIS ChIP-seq数据。