The Vivian L. Smith Department of Neurosurgery, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA.
Center for Stem Cell and Regenerative Medicine, UT Brown Foundation Institute of Molecular Medicine, Houston, TX, USA.
BMC Biol. 2021 Jun 25;19(1):132. doi: 10.1186/s12915-021-01057-6.
Oligodendrocytes, responsible for axon ensheathment, are critical for central nervous system (CNS) development, function, and diseases. OLIG2 is an important transcription factor (TF) that acts during oligodendrocyte development and performs distinct functions at different stages. Previous studies have shown that lncRNAs (long non-coding RNAs; > 200 bp) have important functions during oligodendrocyte development, but their roles have not been systematically characterized and their regulation is not yet clear.
We performed an integrated study of genome-wide OLIG2 binding and the epigenetic modification status of both coding and non-coding genes during three stages of oligodendrocyte differentiation in vivo: neural stem cells (NSCs), oligodendrocyte progenitor cells (OPCs), and newly formed oligodendrocytes (NFOs). We found that 613 lncRNAs have OLIG2 binding sites and are expressed in at least one cell type, which can potentially be activated or repressed by OLIG2. Forty-eight of them have increased expression in oligodendrocyte lineage cells. Predicting lncRNA functions by using a "guilt-by-association" approach revealed that the functions of these 48 lncRNAs were enriched in "oligodendrocyte development and differentiation." Additionally, bivalent genes are known to play essential roles during embryonic stem cell differentiation. We identified bivalent genes in NSCs, OPCs, and NFOs and found that some bivalent genes bound by OLIG2 are dynamically regulated during oligodendrocyte development. Importantly, we unveiled a previously unknown mechanism that, in addition to transcriptional regulation via DNA binding, OLIG2 could self-regulate through the 3' UTR of its own mRNA.
Our studies have revealed the missing links in the mechanisms regulating oligodendrocyte development at the transcriptional level and after transcription. The results of our research have improved the understanding of fundamental cell fate decisions during oligodendrocyte lineage formation, which can enable insights into demyelination diseases and regenerative medicine.
少突胶质细胞负责轴突包绕,对中枢神经系统(CNS)的发育、功能和疾病至关重要。OLIG2 是一种重要的转录因子(TF),在少突胶质细胞发育过程中发挥作用,并在不同阶段发挥不同的功能。先前的研究表明,lncRNAs(长非编码 RNA;>200bp)在少突胶质细胞发育过程中具有重要功能,但它们的作用尚未得到系统表征,其调控也尚不清楚。
我们对体内少突胶质细胞分化的三个阶段(神经干细胞(NSCs)、少突胶质前体细胞(OPCs)和新形成的少突胶质细胞(NFOs))进行了 OLIG2 结合和编码及非编码基因的表观遗传修饰状态的全基因组综合研究。我们发现 613 个 lncRNA 具有 OLIG2 结合位点,并在至少一种细胞类型中表达,这些 lncRNA 可潜在地被 OLIG2 激活或抑制。其中 48 个在少突胶质细胞谱系细胞中表达增加。通过使用“关联定罪”方法预测 lncRNA 功能,发现这 48 个 lncRNA 的功能在“少突胶质细胞发育和分化”中富集。此外,已知双价基因在胚胎干细胞分化过程中发挥重要作用。我们在 NSCs、OPCs 和 NFOs 中鉴定了双价基因,并发现 OLIG2 结合的一些双价基因在少突胶质细胞发育过程中是动态调节的。重要的是,我们揭示了一个以前未知的机制,即在 DNA 结合转录调控之外,OLIG2 还可以通过自身 mRNA 的 3'UTR 进行自我调控。
我们的研究揭示了在转录水平和转录后调节少突胶质细胞发育的机制中缺失的环节。我们的研究结果提高了对少突胶质细胞谱系形成过程中基本细胞命运决定的理解,这可以为脱髓鞘疾病和再生医学提供新的见解。