XLID syndrome gene Med12 promotes Ig isotype switching through chromatin modification and enhancer RNA regulation.
XLID syndrome gene Med12 promotes Ig isotype switching through chromatin modification and enhancer RNA regulation.
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DOI：
10.1126/sciadv.add1466
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发表时间：
2022-11-25
期刊：
影响因子：
13.6
通讯作者：
中科院分区：
文献类型：
--
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转录辅激活因子Med 12通过其激酶模块调节基因表达。在这里，我们显示了一个激酶模块独立的功能的Med 12在CSR。Med 12通过与p300-Jmjd 6/Carm 1共激活因子复合物协作而对超级增强子激活至关重要。Med 12缺失降低了H3 K27乙酰化和eRNA转录，并伴随着AIDS诱导的DNA断裂、S-S突触形成和3′RR-Eμ相互作用的损害。CRISPR-dCas 9介导的增强子激活重建了超级增强子的表观基因组和转录标志，并完全恢复了Med 12缺失缺陷。此外，3′ RR衍生的eRNA对于促进S区表观遗传调节、突触形成以及Med 12和AID向IgH位点的募集至关重要。我们发现XLID综合征相关的Med 12突变在3′RR eRNA转录和CSR方面都有缺陷，这表明B和神经元细胞可能具有细胞特异性超级增强子功能障碍。我们的结论是，Med 12是必不可少的IgH 3′RR激活/eRNA转录，并在艾滋病诱导的抗体基因多样性和基因组不稳定性在B细胞中发挥核心作用。Med 12通过激活IgH 3 'RR增强子调节CSR期间AIDS诱导的DNA断裂和重组。
The transcriptional coactivator Med12 regulates gene expression through its kinase module. Here, we show a kinase module–independent function of Med12 in CSR. Med12 is essential for super-enhancer activation by collaborating with p300-Jmjd6/Carm1 coactivator complexes. Med12 loss decreases H3K27 acetylation and eRNA transcription with concomitant impairment of AID-induced DNA breaks, S-S synapse formation, and 3′RR-Eμ interaction. CRISPR-dCas9–mediated enhancer activation reestablishes the epigenomic and transcriptional hallmarks of the super-enhancer and fully restores the Med12 depletion defects. Moreover, 3′RR-derived eRNAs are critical for promoting S region epigenetic regulation, synapse formation, and recruitment of Med12 and AID to the IgH locus. We find that XLID syndrome–associated Med12 mutations are defective in both 3′RR eRNA transcription and CSR, suggesting that B and neuronal cells may have cell-specific super-enhancer dysfunctions. We conclude that Med12 is essential for IgH 3′RR activation/eRNA transcription and plays a central role in AID-induced antibody gene diversification and genomic instability in B cells. Med12 regulates AID-induced DNA break and recombination during CSR by activating the IgH 3’RR enhancer.
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影响因子：
16
作者：
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通讯作者：
Wysocka, Joanna
DOI：
10.1038/nrm3949
发表时间：
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期刊：
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影响因子：
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