c-Myc-dependent transcriptional regulation of cell cycle and nucleosomal histones during oligodendrocyte differentiation.
c-Myc-dependent transcriptional regulation of cell cycle and nucleosomal histones during oligodendrocyte differentiation.
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DOI：
10.1016/j.neuroscience.2014.01.051
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发表时间：
2014-09-12
期刊：
影响因子：
3.3
通讯作者：
Casaccia, P.
中科院分区：
文献类型：
--
作者：
Magri, L.;Gacias, M.;Wu, M.;Swiss, V. A.;Janssen, W. G.;Casaccia, P.
少突胶质细胞祖细胞（OPCs）具有分裂或抑制生长并在发育中的脑中分化成髓鞘形成的少突胶质细胞的能力。由于它们在成人脑中的高数量和持续增殖能力，OPCs正在被研究为髓鞘修复的潜在靶点，也是脑肿瘤的潜在来源。本研究探讨了在体外培养的OPCs增殖和细胞周期退出之间的关键过渡期发生转录变化的分子调控机制。使用现有数据集的生物信息学分析，我们确定了c-Myc作为这种转变的关键转录调节因子，并使用染色质免疫沉淀法证实了这种转录因子与确定的靶基因的直接结合。c-Myc的表达在增殖的OPCs中升高，其中它还结合到参与细胞周期调节（即Cdc2）或染色体组织（即H2afz）的基因的启动子。c-Myc基因的沉默与靶基因启动子组蛋白乙酰化的降低以及随之而来的基因转录物的减少有关。c-Myc沉默还诱导了抑制性组蛋白甲基化和过早的核外周染色质致密化的总体增加，并促进了OPCs向分化的进展。我们的结论是，c-Myc是一个重要的调制器之间的过渡OPCs的增殖和分化，虽然它的减少是不足以诱导进展成髓鞘表型。
Oligodendrocyte progenitor cells (OPCs) have the ability to divide or to arrest growth and differentiate into myelinating oligodendrocytes in the developing brain. Due to their high number and the persistence of their proliferative capacity in the adult brain, OPCs are being studied as potential targets for myelin repair and also as potential source of brain tumors. This study addresses the molecular mechanisms regulating the transcriptional changes occurring at the critical transition between proliferation and cell cycle exit in cultured OPCs. Using bioinformatic analysis of existing datasets, we identified c-Myc as a key transcriptional regulator of this transition and confirmed direct binding of this transcription factor to identified target genes using chromatin immunoprecipitation. The expression of c-Myc was elevated in proliferating OPCs, where it also bound to the promoter of genes involved in cell cycle regulation (i.e. Cdc2) or chromosome organization (i.e. H2afz). Silencing of c-Myc was associated with decreased histone acetylation at target gene promoters and consequent decrease of gene transcripts. c-Myc silencing induced also a global increase of repressive histone methylation and premature nuclear peripheral chromatin compaction and promoted the progression of OPCs towards differentiation. We conclude that c-Myc is an important modulator of the transition between proliferation and differentiation of OPCs, although its decrease is not sufficient to induce progression into a myelinating phenotype.
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影响因子：
3.7
作者：
Liu J;Sandoval J;Doh ST;Cai L;López-Rodas G;Casaccia P
通讯作者：
Casaccia P
影响因子：
8.8
作者：
Hirvonen, Harri E.;Salonen, Reijo;Sandberg, Minna M.;Vuorio, Eero;Vastrik, Imre;Kotilainen, Esa;Kalimo, Hannu
通讯作者：
Kalimo, Hannu
影响因子：
56.9
作者：
BLACKWELL, TK;KRETZNER, L;WEINTRAUB, H
通讯作者：
WEINTRAUB, H
影响因子：
5.8
作者：
Lachmann, Alexander;Xu, Huilei;Ma'ayan, Avi
通讯作者：
Ma'ayan, Avi
影响因子：
2.8
作者：
Hanson, Hugo H.;Reilly, James E.;Phillips, Greg R.
通讯作者：
Phillips, Greg R.