为了定义心脏细胞发育的多细胞表观和转录图谱，研究人员生成了人类胎儿心脏组织的单细胞染色质可及性图谱。研究人员确定了涉及原代心脏细胞类型的八个主要分化轨迹，每个都与动态转录因子（TF）活动特征有关。研究人员对比了iPSC衍生的心脏细胞类型和体内的对应类型的调控图谱，这使得心外膜细胞的体外分化得到优化。
此外，研究人员解释了基于序列的细胞型染色质可及性概况的深度学习模型，可用于解读潜在的TF模体词库。预测会影响动脉内皮细胞染色质可及性的新突变在先天性心脏病（CHD）病例与对照组中富集。在iPSC中的体外研究验证了被鉴定的变异对预测的发育细胞类型的功能影响。因此，这项工作确定了心脏发育的细胞类型顺式调控序列的决定因素，并确定了CHD中细胞类型特异性调控元件的破坏。
附：英文原文
Title: Integrative single-cell analysis of cardiogenesis identifies developmental trajectories and non-coding mutations in congenital heart disease
Author: Mohamed Ameen, Laksshman Sundaram, Mengcheng Shen, Abhimanyu Banerjee, Soumya Kundu, Surag Nair, Anna Shcherbina, Mingxia Gu, Kitchener D. Wilson, Avyay Varadarajan, Nirmal Vadgama, Akshay Balsubramani, Joseph C. Wu, Jesse M. Engreitz, Kyle Farh, Ioannis Karakikes, Kevin C. Wang, Thomas Quertermous, William J. Greenleaf, Anshul Kundaje
Issue&Volume: 2022/12/22
Abstract: To define the multi-cellular epigenomic and transcriptional landscape of cardiac cellular development, we generated single-cell chromatin accessibility maps of human fetal heart tissues. We identified eight major differentiation trajectories involving primary cardiac cell types, each associated with dynamic transcription factor (TF) activity signatures. We contrasted regulatory landscapes of iPSC-derived cardiac cell types and their in vivo counterparts, which enabled optimization of in vitro differentiation of epicardial cells. Further, we interpreted sequence based deep learning models of cell-type-resolved chromatin accessibility profiles to decipher underlying TF motif lexicons. De novo mutations predicted to affect chromatin accessibility in arterial endothelium were enriched in congenital heart disease (CHD) cases vs. controls. In vitro studies in iPSCs validated the functional impact of identified variation on the predicted developmental cell types. This work thus defines the cell-type-resolved cis-regulatory sequence determinants of heart development and identifies disruption of cell type-specific regulatory elements in CHD.
DOI: 10.1016/j.cell.2022.11.028
Source: https://www.cell.com/cell/fulltext/S0092-8674(22)01503-3