Developmental Chromatin Restriction of Pro-Growth Gene Networks Acts as an Epigenetic Barrier to Axon Regeneration in Cortical Neurons.
Developmental Chromatin Restriction of Pro-Growth Gene Networks Acts as an Epigenetic Barrier to Axon Regeneration in Cortical Neurons.
复制标题
DOI：
10.1002/dneu.22605
复制
发表时间：
2018-10
影响因子：
3
通讯作者：
Blackmore MG
中科院分区：
文献类型：
--
作者：
Venkatesh I;Mehra V;Wang Z;Califf B;Blackmore MG
中枢神经系统中轴突再生的部分原因是成熟神经元内在再生能力的发育下降。轴突生长能力的丧失可能反映了基因表达的广泛变化，但驱动这种转变的机制仍不清楚。染色质可及性已成为其他细胞环境中的关键调节机制，这提高了染色质结构可能导致年龄依赖性再生潜力丧失的可能性。在这里，我们建立了一个集成的生物信息学管道，它将发育动态基因网络的分析与转录因子调控和染色质可及性的全基因组图谱结合起来。当应用于发育中的皮层时，该管道检测到与轴突生长相关的基因子网络中染色质的整体闭合。接下来，我们分析了提供各种促再生转录因子的成熟中枢神经系统神经元。与之前 SOX11 和 KLF7 的结果不同，我们发现 JUN 和 STAT3 的激活形式均不促进实质性皮质脊髓束再生。相应地，JUN 或 STAT3 靶基因中的染色质可及性显着低于 SOX11 和 KLF7 的预测靶基因。最后，我们使用该流程来预测可能缓解生长相关位点染色质限制的先锋因素。总体而言，这种综合分析证实了这样的假设：动态染色质可及性会导致轴突生长能力的发育下降，并影响成人促再生干预的效果，同时也指出选定的先锋因子作为未来组合实验的高优先级候选者。
Axon regeneration in the central nervous system is prevented in part by a developmental decline in the intrinsic regenerative ability of maturing neurons. This loss of axon growth ability likely reflects widespread changes in gene expression, but the mechanisms that drive this shift remain unclear. Chromatin accessibility has emerged as a key regulatory mechanism in other cellular contexts, raising the possibility that chromatin structure may contribute to the age-dependent loss of regenerative potential. Here we establish an integrated bioinformatic pipeline that combines analysis of developmentally dynamic gene networks with transcription factor regulation and genome-wide maps of chromatin accessibility. When applied to the developing cortex, this pipeline detected overall closure of chromatin in sub-networks of genes associated with axon growth. We next analyzed mature CNS neurons that were supplied with various pro-regenerative transcription factors. Unlike prior results with SOX11 and KLF7, here we found that neither JUN nor an activated form of STAT3 promoted substantial corticospinal tract regeneration. Correspondingly, chromatin accessibility in JUN or STAT3 target genes was substantially lower than in predicted targets of SOX11 and KLF7. Finally, we used the pipeline to predict pioneer factors that could potentially relieve chromatin constraints at growth-associated loci. Overall this integrated analysis substantiates the hypothesis that dynamic chromatin accessibility contributes to the developmental decline in axon growth ability and influences the efficacy of pro-regenerative interventions in the adult, while also pointing toward selected pioneer factors as high-priority candidates for future combinatorial experiments.
登录
查看更多内容
影响因子：
3.5
作者：
Blackmore, Murray G.;Moore, Darcie L.;Smith, Robin P.;Goldberg, Jeffrey L.;Bixby, John L.;Lemmon, Vance P.
通讯作者：
Lemmon, Vance P.
影响因子：
5.7
作者：
Cho Y;Cavalli V
通讯作者：
Cavalli V
影响因子：
64.8
作者：
Gaspar-Maia A;Alajem A;Polesso F;Sridharan R;Mason MJ;Heidersbach A;Ramalho-Santos J;McManus MT;Plath K;Meshorer E;Ramalho-Santos M
通讯作者：
Ramalho-Santos M
影响因子：
5.3
作者：
Broude, E;McAtee, M;Bregman, BS
通讯作者：
Bregman, BS
DOI：
10.1093/bioinformatics/btp101
发表时间：
2009-04-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Bindea G;Mlecnik B;Hackl H;Charoentong P;Tosolini M;Kirilovsky A;Fridman WH;Pagès F;Trajanoski Z;Galon J
通讯作者：
Galon J