Successful pregnancy relies directly on the placenta’s complex, dynamic, gene-regulatory networks. Disruption of this vast collection of intercellular and intracellular programs leads to pregnancy complications and developmental defects. In the present study, we generated a comprehensive, spatially resolved, multimodal cell census elucidating the molecular architecture of the first trimester human placenta. We utilized paired single-nucleus (sn)ATAC (assay for transposase accessible chromatin) sequencing and RNA sequencing (RNA-seq), spatial snATAC-seq and RNA-seq, and in situ sequencing and hybridization mapping of transcriptomes at molecular resolution to spatially reconstruct the joint epigenomic and transcriptomic regulatory landscape. Paired analyses unraveled intricate tumor-like gene expression and transcription factor motif programs potentially sustaining the placenta in a hostile uterine environment; further investigation of gene-linked cis-regulatory elements revealed heightened regulatory complexity that may govern trophoblast differentiation and placental disease risk. Complementary spatial mapping techniques decoded these programs within the placental villous core and extravillous trophoblast cell column architecture while simultaneously revealing niche-establishing transcriptional elements and cell–cell communication. Finally, we computationally imputed genome-wide, multiomic single-cell profiles and spatially characterized the placental chromatin accessibility landscape. This spatially resolved, single-cell multiomic framework of the first trimester human placenta serves as a blueprint for future studies on early placental development and pregnancy.

成功怀孕直接取决于胎盘复杂、动态的基因调控网络。破坏这一庞大的细胞间和细胞内程序会导致妊娠并发症和发育缺陷。在本研究中，我们生成了一个全面的、空间分辨的多模式细胞普查，阐明了妊娠早期人类胎盘的分子结构。我们利用配对单核 （sn）ATAC （转座酶可及染色质测定） 测序和 RNA 测序 （RNA-seq） 、空间 snATAC-seq 和 RNA-seq，以及分子分辨率转录组的原位测序和杂交作图，在空间上重建联合表观基因组和转录组调控景观。配对分析揭示了错综复杂的肿瘤样基因表达和转录因子基序程序，这些程序可能在恶劣的子宫环境中维持胎盘;对基因连锁顺式调控元件的进一步研究揭示了可能控制滋养层分化和胎盘疾病风险的调控复杂性增加。互补的空间映射技术在胎盘绒毛核心和绒毛外滋养层细胞柱结构中解码了这些程序，同时揭示了建立生态位的转录元件和细胞间通讯。最后，我们计算估算了全基因组、多组学单细胞谱，并在空间上表征了胎盘染色质可及性景观。这种空间分辨的人类胎盘单细胞多组学框架是未来早期胎盘发育和妊娠研究的蓝图。