Departments of Pathology and Cell Biology, Neurology, and Neuroscience, Center for Motor Neuron Biology and Disease, Columbia Stem Cell Initiative, Columbia University Medical Center, 630 W 168 Street, New York, NY 10032, USA.
Department of Biology, New York University. 100 Washington Square East, New York, NY 10003, USA.
Nat Neurosci. 2013 Sep;16(9):1191-1198. doi: 10.1038/nn.3490. Epub 2013 Aug 18.
Hox genes controlling motor neuron subtype identity are expressed in rostrocaudal patterns that are spatially and temporally collinear with their chromosomal organization. Here we demonstrate that Hox chromatin is subdivided into discrete domains that are controlled by rostrocaudal patterning signals that trigger rapid, domain-wide clearance of repressive histone H3 Lys27 trimethylation (H3K27me3) polycomb modifications. Treatment of differentiating mouse neural progenitors with retinoic acid leads to activation and binding of retinoic acid receptors (RARs) to the Hox1-Hox5 chromatin domains, which is followed by a rapid domain-wide removal of H3K27me3 and acquisition of cervical spinal identity. Wnt and fibroblast growth factor (FGF) signals induce expression of the Cdx2 transcription factor that binds and clears H3K27me3 from the Hox1-Hox9 chromatin domains, leading to specification of brachial or thoracic spinal identity. We propose that rapid clearance of repressive modifications in response to transient patterning signals encodes global rostrocaudal neural identity and that maintenance of these chromatin domains ensures the transmission of positional identity to postmitotic motor neurons later in development.
控制运动神经元亚型身份的 Hox 基因以与它们的染色体组织空间和时间一致的头尾模式表达。在这里，我们证明 Hox 染色质被细分为离散的域，这些域受头尾模式信号的控制，这些信号触发抑制性组蛋白 H3 赖氨酸 27 三甲基化（H3K27me3）多梳修饰的快速、全域清除。用维甲酸处理分化的小鼠神经祖细胞会导致维甲酸受体（RAR）与 Hox1-Hox5 染色质域的激活和结合，随后是 H3K27me3 的全域清除和获得颈脊髓身份。Wnt 和成纤维细胞生长因子（FGF）信号诱导 Cdx2 转录因子的表达，该转录因子结合并从 Hox1-Hox9 染色质域中清除 H3K27me3，导致臂或胸脊髓身份的指定。我们提出，对短暂模式信号的快速清除抑制修饰以响应编码全局头尾神经身份，并且维持这些染色质域确保在发育后期将位置身份传递给有丝分裂后的运动神经元。
