Single-cell transcriptome and accessible chromatin dynamics during endocrine pancreas development.
Single-cell transcriptome and accessible chromatin dynamics during endocrine pancreas development.
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DOI：
10.1073/pnas.2201267119
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发表时间：
2022-06-28
影响因子：
11.1
通讯作者：
中科院分区：
文献类型：
--
作者：
尽管胰腺生物学已经取得了几十年的进展，但胰腺内分泌祖细胞的分子特征仍然难以捉摸，不同的分泌激素的胰岛内分泌细胞如何选择它们的命运在很大程度上是未知的。一种长期的观点认为，导管上皮含有双能前体细胞，这是内分泌前体细胞的起源。在这里，我们提供了缺乏双能祖细胞的证据，并建议从导管细胞直接发展内分泌谱系。我们的结果还表明，内分泌分化不需要在Neurog3表达之前在导管细胞中进行染色质“启动”。对于发育生物学家来说，描绘协调细胞类型规范的基因调控网络是一个持续的挑战。单细胞分析提供了解决这些挑战的机会，并加快了稀有细胞谱系关系的发现和层级谱系决策的机制。在这里，我们描述了使用单细胞转录、结合遗传标记的染色质可及性分析和基于细胞术的细胞纯化的小鼠胰腺内分泌细胞分化的分子分析。我们发现了描绘β-，α-和δ-细胞谱系的转录因子网络。通过基因组足迹分析，我们确定了以前所未有的分辨率控制胰腺细胞发育的转录因子-调控DNA相互作用。我们的分析表明，转录因子Neurog3可能作为一种先驱转录因子来指定胰腺内分泌谱系。这些发现可能会改进从干细胞等可再生来源产生替代内分泌细胞用于糖尿病治疗的方案。
Despite decades of progress in pancreas biology, the molecular features of pancreatic endocrine progenitors remain elusive, and how different hormone-producing islet endocrine cells choose their fate is largely unknown. A longstanding view suggests that ductal epithelium harbors bipotent progenitor cells, which are the origin of endocrine progenitors. Here, we provide evidence for the absence of a bipotent progenitor and suggest direct development of endocrine lineage from duct cells. Our results also suggest that chromatin “priming” in duct cells prior to Neurog3 expression is not required for endocrine differentiation. Delineating gene regulatory networks that orchestrate cell-type specification is a continuing challenge for developmental biologists. Single-cell analyses offer opportunities to address these challenges and accelerate discovery of rare cell lineage relationships and mechanisms underlying hierarchical lineage decisions. Here, we describe the molecular analysis of mouse pancreatic endocrine cell differentiation using single-cell transcriptomics, chromatin accessibility assays coupled to genetic labeling, and cytometry-based cell purification. We uncover transcription factor networks that delineate β-, α-, and δ-cell lineages. Through genomic footprint analysis, we identify transcription factor–regulatory DNA interactions governing pancreatic cell development at unprecedented resolution. Our analysis suggests that the transcription factor Neurog3 may act as a pioneer transcription factor to specify the pancreatic endocrine lineage. These findings could improve protocols to generate replacement endocrine cells from renewable sources, like stem cells, for diabetes therapy.
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影响因子：
11.8
作者：
Arda, H. Efsun;Benitez, Cecil M.;Kim, Seung K.
通讯作者：
Kim, Seung K.
影响因子：
29
作者：
Chakravarthy H;Gu X;Enge M;Dai X;Wang Y;Damond N;Downie C;Liu K;Wang J;Xing Y;Chera S;Thorel F;Quake S;Oberholzer J;MacDonald PE;Herrera PL;Kim SK
通讯作者：
Kim SK
影响因子：
8.8
作者：
Baek S;Goldstein I;Hager GL
通讯作者：
Hager GL
影响因子：
16.6
作者：
Byrnes LE;Wong DM;Subramaniam M;Meyer NP;Gilchrist CL;Knox SM;Tward AD;Ye CJ;Sneddon JB
通讯作者：
Sneddon JB
影响因子：
4.6
作者：
Bastidas-Ponce, Aimee;Tritschler, Sophie;Bakhti, Mostafa
通讯作者：
Bakhti, Mostafa