GFI1 regulates hair cell differentiation by acting as an off-DNA transcriptional co-activator of ATOH1, and a DNA-binding repressor.
GFI1 regulates hair cell differentiation by acting as an off-DNA transcriptional co-activator of ATOH1, and a DNA-binding repressor.
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DOI：
10.1038/s41598-022-11931-0
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发表时间：
2022-05-12
影响因子：
4.6
通讯作者：
Groves AK
中科院分区：
文献类型：
--
作者：
Jen HI;Singh S;Tao L;Maunsell HR;Segil N;Groves AK
GFI1 是一种锌指转录因子，是耳蜗毛细胞分化和存活所必需的。小鼠中 Gfi1 的缺失显着降低了数百个毛细胞基因的表达：这是一个令人惊讶的结果，因为 GFI1 通常通过将组蛋白去甲基酶和甲基转移酶招募到其靶标来充当转录抑制因子。为了了解 GFI1 促进毛细胞分化的机制，我们使用 CUT&RUN 来确定 GFI1 和 ATOH1 在毛细胞中的直接靶标。我们发现 GFI1 以两种不同的方式调节毛细胞分化——首先，GFI1 和 ATOH1 可以与毛细胞基因中的相同调控元件结合，但是 ATOH1 在许多这些区域中直接结合其目标 DNA 基序，而 GFI1 则不能。相反，它似乎通过充当不直接结合 DNA 的复合物的一部分来增强 ATOH1 的转录活性。其次，GFI1 可以发挥其更典型的作用，作为毛细胞中的直接 DNA 结合转录抑制因子。它在这里抑制非毛细胞基因，包括许多神经元基因。总之，我们的结果阐明了 GFI1 在毛细胞发育和毛细胞重编程策略中的功能。
GFI1 is a zinc finger transcription factor that is necessary for the differentiation and survival of hair cells in the cochlea. Deletion of Gfi1 in mice significantly reduces the expression of hundreds of hair cell genes: this is a surprising result, as GFI1 normally acts as a transcriptional repressor by recruiting histone demethylases and methyltransferases to its targets. To understand the mechanisms by which GFI1 promotes hair cell differentiation, we used CUT&RUN to identify the direct targets of GFI1 and ATOH1 in hair cells. We found that GFI1 regulates hair cell differentiation in two distinct ways—first, GFI1 and ATOH1 can bind to the same regulatory elements in hair cell genes, but while ATOH1 directly binds its target DNA motifs in many of these regions, GFI1 does not. Instead, it appears to enhance ATOH1’s transcriptional activity by acting as part of a complex in which it does not directly bind DNA. Second, GFI1 can act in its more typical role as a direct, DNA-binding transcriptional repressor in hair cells; here it represses non-hair cell genes, including many neuronal genes. Together, our results illuminate the function of GFI1 in hair cell development and hair cell reprogramming strategies.
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Liu, Q.;Basu, S.;Qiu, Y.;Tang, F.;Dong, F.
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DOI：
10.1073/pnas.0804863106
发表时间：
2009-02-03
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