School of Basic Medical Sciences, Anhui Medical University, Hefei, China.
BMC Genomics. 2024 Feb 29;25(1):225. doi: 10.1186/s12864-024-10120-9.
In epigenetic modification, histone modification and DNA methylation coordinate the regulation of spermatogonium. Not only can methylcytosine dioxygenase 1 (TET1) function as a DNA demethylase, converting 5-methylcytosine to 5-hydroxymethylcytosine, it can also form complexes with other proteins to regulate gene expression. H3K27me3, one of the common histone modifications, is involved in the regulation of stem cell maintenance and tumorigenesis by inhibiting gene transcription.
we examined JMJD3 at both mRNA and protein levels and performed Chip-seq sequencing of H3K27me3 in TET1 overexpressing cells to search for target genes and signaling pathways of its action.
This study has found that JMJD3 plays a leading role in spermatogonia self-renewal and proliferation: at one extreme, the expression of the self-renewal gene GFRA1 and the proliferation-promoting gene PCNA was upregulated following the overexpression of JMJD3 in spermatogonia; at the other end of the spectrum, the expression of differentiation-promoting gene DAZL was down-regulated. Furthermore, the fact that TET1 and JMJD3 can form a protein complex to interact with H3K27me3 has also been fully proven. Then, through analyzing the sequencing results of CHIP-Seq, we found that TET1 targeted Pramel3 when it interacted with H3K27me3. Besides, TET1 overexpression not only reduced H3K27me3 deposition at Pramel3, but promoted its transcriptional activation as well, and the up-regulation of Pramel3 expression was verified in JMJD3-overexpressing spermatogonia.
In summary, our study identified a novel link between TET1 and H3K27me3 and established a Tet1-JMJD3-H3K27me3-Pramel3 axis to regulate spermatogonia self-renewal and proliferation. Judging from the evidence offered above, we can safely conclude that this study provides new ideas for further research regarding the mechanism of spermatogenesis and spermatogenesis disorders on an apparent spectrum.
在表观遗传修饰中，组蛋白修饰和 DNA 甲基化协同调节精原细胞。甲基胞嘧啶双加氧酶 1（TET1）不仅可以作为 DNA 去甲基化酶，将 5-甲基胞嘧啶转化为 5-羟甲基胞嘧啶，还可以与其他蛋白质形成复合物来调节基因表达。H3K27me3 是常见的组蛋白修饰之一，它通过抑制基因转录参与干细胞维持和肿瘤发生的调节。
我们在 mRNA 和蛋白质水平上检查了 JMJD3，并对 TET1 过表达细胞中的 H3K27me3 进行了 Chip-seq 测序，以寻找其作用的靶基因和信号通路。
本研究发现 JMJD3 在精原细胞自我更新和增殖中起主导作用：一方面，JMJD3 在精原细胞中的过表达上调了自我更新基因 GFRA1 和促进增殖基因 PCNA 的表达；另一方面，促进分化基因 DAZL 的表达下调。此外，充分证明了 TET1 和 JMJD3 可以形成蛋白质复合物与 H3K27me3 相互作用。然后，通过分析 CHIP-Seq 的测序结果，我们发现 TET1 在与 H3K27me3 相互作用时靶向 Pramel3。此外，TET1 的过表达不仅降低了 Pramel3 上的 H3K27me3 沉积，而且促进了其转录激活，在 JMJD3 过表达的精原细胞中验证了 Pramel3 表达的上调。
综上所述，我们的研究确定了 TET1 和 H3K27me3 之间的新联系，并建立了 Tet1-JMJD3-H3K27me3-Pramel3 轴来调节精原细胞的自我更新和增殖。从提供的证据来看，我们可以有把握地得出结论，这项研究为进一步研究精子发生和精子发生障碍的机制提供了新的思路，这些机制在明显的谱上是相关的。
