Genomics of sexual cell fate transdifferentiation in the mouse gonad.
Genomics of sexual cell fate transdifferentiation in the mouse gonad.
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DOI：
10.1093/g3journal/jkac267
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发表时间：
2022-12-01
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--
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哺乳动物的性别决定取决于胎儿双能性腺中形成雄性支持细胞或雌性颗粒细胞之间的细胞命运决定。虽然这一决定通常是永久性的，但关键细胞命运调节因子如转录因子Dmrt 1和Foxl2的丧失可导致出生后从支持细胞转分化为颗粒细胞样细胞（Dmrt 1），反之亦然（Foxl2）。在这里，我们研究的机制，男性到女性的转分化的小鼠携带无效突变的Dmrt 1或点突变，R111G，改变DNA结合基序，并导致人类XY性腺发育不全和性逆转。我们首先定义基因在转分化过程中的错误表达，然后表明，女性转录调控驱动转分化的突变体XY性腺（ESR2，LRH 1，FOXL2）结合染色质位点相关的那些通常结合在XX卵巢。接下来，我们定义了转分化开始时的基因表达变化和异常染色质区室，这可能有助于破坏细胞命运并启动转分化过程。我们在小鼠中模拟了R111G突变，并表明它导致显性性腺发育不全，类似于其人类表型，但不太严重。我们发现R111G部分使睾丸转录组女性化，并导致体内DMRT 1结合特异性的显性破坏。这些数据有助于阐明性细胞命运维持被破坏时转分化是如何发生的，并确定可能在转分化过程中发挥关键作用的染色质位点和转录本。
Sex determination in mammals hinges on a cell fate decision in the fetal bipotential gonad between formation of male Sertoli cells or female granulosa cells. While this decision normally is permanent, loss of key cell fate regulators such as the transcription factors Dmrt1 and Foxl2 can cause postnatal transdifferentiation from Sertoli to granulosa-like (Dmrt1) or vice versa (Foxl2). Here, we examine the mechanism of male-to-female transdifferentiation in mice carrying either a null mutation of Dmrt1 or a point mutation, R111G, that alters the DNA-binding motif and causes human XY gonadal dysgenesis and sex reversal. We first define genes misexpressed during transdifferentiation and then show that female transcriptional regulators driving transdifferentiation in the mutant XY gonad (ESR2, LRH1, FOXL2) bind chromatin sites related to those normally bound in the XX ovary. We next define gene expression changes and abnormal chromatin compartments at the onset of transdifferentiation that may help destabilize cell fate and initiate the transdifferentiation process. We model the R111G mutation in mice and show that it causes dominant gonadal dysgenesis, analogous to its human phenotype but less severe. We show that R111G partially feminizes the testicular transcriptome and causes dominant disruption of DMRT1 binding specificity in vivo. These data help illuminate how transdifferentiation occurs when sexual cell fate maintenance is disrupted and identify chromatin sites and transcripts that may play key roles in the transdifferentiation process.
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