Combining the chromatin accessibility dataset with the transcriptome dataset, finer distinctions can be made to elucidate cellular heterogeneity. For example, intermediate progenitor cells were designated as a single cluster by transcriptome, while the same population of cells was divided into three subclusters by SNARE-seq (Chen
et al. 2019). Meanwhile, the cell-type boundaries were relatively unclear and some minor cell types were not detected when only referred by the single-cell ATAC-seq dataset (Chen
et al. 2019). With single-cell pair-wise datasets, the direct correlation of gene expression with the accessibility of
cis-regulatory elements was confirmed for cell type specific genes (Chen
et al. 2019; Trevino
et al. 2021; Zhu
et al. 2019). By identifying potential regulatory programs during neurogenesis and pathogenesis, we can evaluate the risks of neural disorder diseases at much earlier stages. Trevino
et al. used the 10X Next GEM Single Cell Multiome ATAC + Gene Expression kit to analyze the human fetal cerebral cortex, and they found that the chromatin states of lineage-defining transcription factors are already accessible before the progenitor cells enter the cell cycle (Trevino
et al. 2021). The researchers also infer the regulatory impact of autism spectrum disorder (ASD) relevant non-coding genetic variants in different cell types based on the chromatin accessibility patterns, including identification of loss of function of NFIA during the pathogenesis of ASD (Iossifov
et al. 2014). Specifically, one G to A mutation in the enhancer, located within the intron of NFIA, may disrupt accessibility and silence NFIA in some excitatory neurons (Trevino
et al. 2021). In addition to marker genes, the ATAC-seq peaks can also act as biomarkers for specific cell clusters. In SHARE-seq, the authors also identified temporal sequential activation of genome regions and gene expression in mouse skin development. Therefore, the chromatin accessibility of enhancers has the potential to foreshadow gene expression and predict lineage choice prior to the expression of key genes (Ma
et al. 2020b).