Nazarieh Maryam, Hoeppner Marc, Helms Volkhard
Institute of Clinical Molecular Biology, Christian-Albrecht-University of Kiel, Kiel, Germany.
Center for Bioinformatics, Saarland University, Saarbruecken, Germany.
Front Bioinform. 2021 Jul 19;1:653054. doi: 10.3389/fbinf.2021.653054. eCollection 2021.
A blood cell lineage consists of several consecutive developmental stages starting from the pluri- or multipotent stem cell to a state of terminal differentiation. Despite their importance for human biology, the regulatory pathways and gene networks that govern these differentiation processes are not yet fully understood. This is in part due to challenges associated with delineating the interactions between transcription factors (TFs) and their corresponding target genes. A possible step forward in this case is provided by the increasing amount of expression data, as a basis for linking differentiation stages and gene activities. Here, we present a novel hierarchical approach to identify characteristic expression peak patterns that global regulators excert along the differentiation path of cell lineages. Based on such simple patterns, we identified cell state-specific marker genes and extracted TFs that likely drive their differentiation. Integration of the mean expression values of stage-specific "key player" genes yielded a distinct peaking pattern for each lineage that was used to identify further genes in the dataset which behave similarly. Incorporating the set of TFs that regulate these genes led to a set of stage-specific regulators that control the biological process of cell fate. As proof of concept, we considered two expression datasets covering key differentiation events in blood cell formation of mice.
血细胞谱系由几个连续的发育阶段组成，从多能或多潜能干细胞开始，直至终末分化状态。尽管它们对人类生物学很重要，但控制这些分化过程的调控途径和基因网络尚未完全了解。部分原因是在描绘转录因子（TFs）与其相应靶基因之间的相互作用时存在挑战。在这种情况下，越来越多的表达数据为将分化阶段与基因活性联系起来提供了可能的前进方向。在这里，我们提出了一种新颖的分层方法，以识别全局调节因子在细胞谱系分化路径上施加的特征性表达峰值模式。基于这些简单模式，我们鉴定了细胞状态特异性标记基因，并提取了可能驱动其分化的转录因子。阶段特异性“关键参与者”基因的平均表达值整合产生了每个谱系独特的峰值模式，用于识别数据集中表现相似的其他基因。纳入调节这些基因的转录因子集合导致了一组控制细胞命运生物学过程的阶段特异性调节因子。作为概念验证，我们考虑了两个涵盖小鼠血细胞形成关键分化事件的表达数据集。
