Department of Biochemistry, School of Life Sciences, University of Hyderabad, Hyderabad 500019, Telangana, India.
Department of Pathology, University of Cambridge, Cambridge CB2 1QP, UK.
Int J Mol Sci. 2024 Sep 19;25(18):10073. doi: 10.3390/ijms251810073.
In the realm of hematopoiesis, hematopoietic stem cells (HSCs) serve as pivotal entities responsible for generating various blood cell types, initiating both the myeloid and lymphoid branches within the hematopoietic lineage. This intricate process is marked by genetic variations that underscore the crucial role of genes in regulating cellular functions and interactions. Recognizing the significance of genetic factors in this context, this article delves into a genetic perspective, aiming to unravel the biological factors that govern the transition from one cell's fate to another within the hematopoietic system. To gain deeper insights into the genetic traits of three distinct blood cell types-HSCs, erythroblasts (EBs), and megakaryocytes (MKs)-we conducted a comprehensive transcriptomic analysis. Leveraging diverse hematopoietic cell datasets from healthy individuals, sourced from The BLUEPRINT consortium, our investigation targeted the identification of genetic variants responsible for changes in gene expression levels and epigenetic modifications across the entire human genome in each of these cell types. The total number of normalized expressed transcripts includes 14,233 novel trinity lncRNAs, 13,749 mRNAs, and 3092 lncRNAs. This scrutiny revealed a total of 31,074 transcripts, with a notable revelation that 14,233 of them were previously unidentified or novel lncRNAs, highlighting a substantial reservoir of genetic information yet to be explored. Examining their expression across distinct lineages further unveiled 2845 differentially expressed (DE) mRNAs and 354 DE long noncoding RNAs (lncRNAs) notably enriched among the three distinct blood cell types: HSCs, EBs, and MKs. Our investigation extended beyond mRNA to focus on the dynamic expression of lncRNAs, revealing a well-defined pattern that played a significant role in regulating differentiation and cell-fate specification. This coordination of lncRNA dynamics extended to aberrations in both mRNA and lncRNA transcriptomes within HSCs, EBs, and MKs. We specifically characterized lncRNAs with preferential expression in HSCs, as well as in various downstream differentiated lineage progenitors of EBs and MKs, providing a comprehensive perspective on lncRNAs in human hematopoietic cells. Notably, the expression of lncRNAs exhibited substantial cell-to-cell variation, a phenomenon discernible only through single-cell analysis. The comparative analysis undertaken in this study provides valuable insights into the distinctive genetic signatures guiding the differentiation of these crucial hematopoietic cell types.
在造血领域，造血干细胞（HSCs）是生成各种血细胞类型的关键实体，启动造血谱系中的骨髓和淋巴两个分支。这个复杂的过程由基因变异标记，突出了基因在调节细胞功能和相互作用中的关键作用。鉴于遗传因素在这方面的重要性，本文深入探讨了遗传视角，旨在揭示控制造血系统中一个细胞命运向另一个细胞命运转变的生物学因素。为了更深入地了解三种不同血细胞类型——造血干细胞、红细胞（EBs）和巨核细胞（MKs）的遗传特征，我们进行了全面的转录组分析。利用来自健康个体的不同造血细胞数据集，这些数据来源于 BLUEPRINT 联盟，我们的研究旨在确定负责这些细胞类型中整个人类基因组中基因表达水平和表观遗传修饰变化的遗传变异。标准化表达转录本的总数包括 14233 个新的三位一体 lncRNA、13749 个 mRNA 和 3092 个 lncRNA。这项细致的研究总共揭示了 31074 个转录本，其中一个显著的发现是，其中 14233 个是以前未被识别或新的 lncRNA，这突显了大量有待探索的遗传信息。进一步检查它们在不同谱系中的表达情况，揭示了 2845 个差异表达（DE）mRNA 和 354 个 DE 长非编码 RNA（lncRNA），这些基因在三种不同的血细胞类型中显著富集：造血干细胞、EB 和 MK。我们的研究不仅局限于 mRNA，还关注 lncRNA 的动态表达，揭示了一个明确的模式，在调节分化和细胞命运特化方面发挥了重要作用。这种 lncRNA 动力学的协调延伸到 HSCs、EB 和 MK 中 mRNA 和 lncRNA 转录本的异常。我们特别描述了在 HSCs 中优先表达的 lncRNA，以及在 EBs 和 MKs 的各种下游分化谱系祖细胞中优先表达的 lncRNA，为人类造血细胞中的 lncRNA 提供了全面的视角。值得注意的是，lncRNA 的表达存在显著的细胞间变异性，这种现象只有通过单细胞分析才能识别。本研究中的比较分析为指导这些关键造血细胞类型分化的独特遗传特征提供了有价值的见解。
