Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
Department of Neurosciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
Proc Natl Acad Sci U S A. 2021 Mar 23;118(12). doi: 10.1073/pnas.2025196118.
Specification of Sox2 proneurosensory progenitors within otic ectoderm is a prerequisite for the production of sensory cells and neurons for hearing. However, the underlying molecular mechanisms driving this lineage specification remain unknown. Here, we show that the Brg1-based SWI/SNF chromatin-remodeling complex interacts with the neurosensory-specific transcriptional regulators Eya1/Six1 to induce expression and promote proneurosensory-lineage specification. Ablation of the ATPase-subunit Brg1 or both Eya1/Six1 results in loss of expression and lack of neurosensory identity, leading to abnormal apoptosis within the otic ectoderm. Brg1 binds to two of three distal 3' enhancers occupied by Six1, and Brg1-binding to these regions depends on Eya1-Six1 activity. We demonstrate that the activity of these enhancers in otic neurosensory cells specifically depends on binding to Six1. Furthermore, genome-wide and transcriptome profiling indicate that Brg1 may suppress apoptotic factor to inhibit apoptosis. Together, our findings reveal an essential role for Brg1, its downstream pathways, and their interactions with Six1/Eya1 in promoting proneurosensory fate induction in the otic ectoderm and subsequent neuronal lineage commitment and survival of otic cells.
在耳胚外胚层中特异性指定 Sox2 神经前体细胞是产生听觉感觉细胞和神经元的前提。然而，驱动这种谱系特化的潜在分子机制仍不清楚。在这里，我们表明基于 Brg1 的 SWI/SNF 染色质重塑复合物与神经感觉特异性转录调节剂 Eya1/Six1 相互作用，诱导 表达并促进神经前体细胞谱系特化。ATP 酶亚基 Brg1 或 Eya1/Six1 的缺失导致 表达的丧失和缺乏神经感觉特性，导致耳胚外胚层内异常细胞凋亡。Brg1 与 Six1 占据的三个远端 3'增强子中的两个结合，并且 Brg1 与这些区域的结合取决于 Eya1-Six1 活性。我们证明这些 增强子在耳神经感觉细胞中的活性特异性依赖于与 Six1 的结合。此外，全基因组和转录组分析表明，Brg1 可能抑制凋亡因子 以抑制细胞凋亡。总之，我们的研究结果揭示了 Brg1 及其下游途径及其与 Six1/Eya1 的相互作用在促进耳胚外胚层中神经前体细胞命运诱导以及随后的神经元谱系决定和耳细胞存活中的重要作用。
