Sexual Dimorphism of Early Transcriptional Reprogramming in Dorsal Root Ganglia After Peripheral Nerve Injury.
Sexual Dimorphism of Early Transcriptional Reprogramming in Dorsal Root Ganglia After Peripheral Nerve Injury.
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周围神经损伤后背根神经节早期转录重编程的性别二型性。
DOI：
10.3389/fnmol.2021.779024
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发表时间：
2021
影响因子：
4.8
通讯作者：
Shubayev VI
中科院分区：
文献类型：
--
作者：
Chernov AV;Shubayev VI
周围神经损伤导致背根神经节(DRG)一级神经元和辅助细胞全基因组转录重编程。越来越多的实验证据表明，神经损伤后过程的开始和机制原理是性二态的。我们研究了在坐骨神经切断后24小时内，两性小鼠背根神经节早期转录事件的大部分未被研究的方面。使用高深度RNA测序(5000万次/样本)来精确定位与再生、免疫反应、生物能量和感觉功能相关的性二态变化，我们发现男性DRG相对于女性DRG的转录变化数量更多。在男性中，离子通道转录物的下降伴随着TLR、趋化因子和CSF1受体轴诱导的先天免疫级联反应，以及由SOX、Twist1/2和Pax5/9转录因子驱动的强大的再生程序。女性表现出神经损伤特异性的肌动蛋白2网络转录共激活。预测的上游调节和互动网络强调了新的表观遗传因素的作用和与性染色体的遗传联系作为轴突切断后基因调控的标志。我们将表观遗传X染色体失活与免疫反应活动的调节联系起来，这在女性中是独一无二的。MMPADAMTS金属蛋白酶及其内在的X连锁调节因子TIMP1的性别二态调节有助于细胞外基质重塑，整合了促再生和免疫功能。Lexis1非编码RNA参与LXR介导的脂代谢，是一种新的神经损伤标志物。总之，我们的数据确定了独特的性别特异性周围神经损伤调控的早期反应触发因素，以获得对女性和男性流行的感觉神经病的起源的机械性见解。
Peripheral nerve injury induces genome-wide transcriptional reprogramming of first-order neurons and auxiliary cells of dorsal root ganglia (DRG). Accumulating experimental evidence suggests that onset and mechanistic principles of post-nerve injury processes are sexually dimorphic. We examined largely understudied aspects of early transcriptional events in DRG within 24 h after sciatic nerve axotomy in mice of both sexes. Using high-depth RNA sequencing (>50 million reads/sample) to pinpoint sexually dimorphic changes related to regeneration, immune response, bioenergy, and sensory functions, we identified a higher number of transcriptional changes in male relative to female DRG. In males, the decline in ion channel transcripts was accompanied by the induction of innate immune cascades via TLR, chemokine, and Csf1-receptor axis and robust regenerative programs driven by Sox, Twist1/2, and Pax5/9 transcription factors. Females demonstrated nerve injury-specific transcriptional co-activation of the actinin 2 network. The predicted upstream regulators and interactive networks highlighted the role of novel epigenetic factors and genetic linkage to sex chromosomes as hallmarks of gene regulation post-axotomy. We implicated epigenetic X chromosome inactivation in the regulation of immune response activity uniquely in females. Sexually dimorphic regulation of MMP/ADAMTS metalloproteinases and their intrinsic X-linked regulator Timp1 contributes to extracellular matrix remodeling integrated with pro-regenerative and immune functions. Lexis1 non-coding RNA involved in LXR-mediated lipid metabolism was identified as a novel nerve injury marker. Together, our data identified unique early response triggers of sex-specific peripheral nerve injury regulation to gain mechanistic insights into the origin of female- and male-prevalent sensory neuropathies.
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影响因子：
5.1
作者：
Ahlström FHG;Mätlik K;Viisanen H;Blomqvist KJ;Liu X;Lilius TO;Sidorova Y;Kalso EA;Rauhala PV
通讯作者：
Rauhala PV
影响因子：
7.4
作者：
Fu ES;Zhang YP;Sagen J;Candiotti KA;Morton PD;Liebl DJ;Bethea JR;Brambilla R
通讯作者：
Brambilla R
影响因子：
4.8
作者：
Chernov, Andrei V.;Sounni, Nor Eddine;Strongin, Alex Y.
通讯作者：
Strongin, Alex Y.
影响因子：
5.3
作者：
García-Añoveros, J;Samad, TA;Corey, DR
通讯作者：
Corey, DR
影响因子：
7.8
作者：
Cavalli, V;Kujala, P;Goldstein, LSB
通讯作者：
Goldstein, LSB