美国加州大学伯克利分校的Nir Yosef和旧金山分校的Nadav Ahituv等研究人员合作鉴定并表征了驱动神经诱导的调控元件。这一研究成果在线发表于2019年10月17日的《细胞—干细胞》。

利用人类多能干细胞（hPSC）的神经诱导作为范例，研究人员通过使用RNA测序（RNA-seq）、染色质免疫沉淀测序（ChIP-seq）以及转座酶可及性染色质测序（ATAC-seq ）测试了在早期神经分化过程中的七个时间点。

研究人员发现，DNA可及性的变化先于H3K27ac，随后是基因表达的变化。通过使用大规模平行报道基因分析（MPRA）在所有七个时间点测试2464个候选调控序列的活性，研究人员显示这些序列中的许多序列具有与各自细胞内源基因表达和染色质变化相关的时间活跃模式。研究人员结合所有基因组和MPRA数据的优先排序方法进一步确定了驱动神经命运的关键转录因子。

这些结果提供了基因和调控元件的综合资源，即这些基因和调控元件可以在分化过程中协调神经诱导并阐明时序框架。

据了解，表观基因调控和谱系特异性基因表达共同作用以驱动细胞分化，但这些过程之间的时序相互作用在很大程度上尚不清楚。

附：英文原文

Title: Identification and Massively Parallel Characterization of Regulatory Elements Driving Neural Induction

Author: Fumitaka Inoue, Anat Kreimer, Tal Ashuach, Nadav Ahituv, Nir Yosef

Issue&Volume: 17 October 2019

Abstract: 

Epigenomic regulation and lineage-specific gene expression act in concert to drive cellular differentiation, but the temporal interplay between these processes is largely unknown. Using neural induction from human pluripotent stem cells (hPSCs) as a paradigm, we interrogated these dynamics by performing RNA sequencing (RNA-seq), chromatin immunoprecipitation sequencing (ChIP-seq), and assay for transposase accessible chromatin using sequencing (ATAC-seq) at seven time points during early neural differentiation. We found that changes in DNA accessibility precede H3K27ac, which is followed by gene expression changes. Using massively parallel reporter assays (MPRAs) to test the activity of 2,464 candidate regulatory sequences at all seven time points, we show that many of these sequences have temporal activity patterns that correlate with their respective cell-endogenous gene expression and chromatin changes. A prioritization method incorporating all genomic and MPRA data further identified key transcription factors involved in driving neural fate. These results provide a comprehensive resource of genes and regulatory elements that orchestrate neural induction and illuminate temporal frameworks during differentiation.

DOI: 10.1016/j.stem.2019.09.010

Source: https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(19)30421-7