Authors
Zhicong Liao, Mimi Zhang, Brian Y Soong, Bohan Zhu, Linda L Boshans, Ke Wang, Miguel Quijada-Álamo, Ifeoma Osakwe, Zhe Wang, Persephone Fiore, Dan Hasson, Elvin Wagenblast, Sai Ma
Published in
bioRxiv : the preprint server for biology. Oct 11, 2026. Epub Oct 11, 2026.
Abstract
Human fetal haematopoiesis requires developmental potential to be encoded before lineage identity becomes transcriptionally apparent, but whether three-dimensional genome architecture provides such information is unknown. Here we develop ChromE-seq, a scalable single-cell assay that jointly profiles chromatin conformation and transcription, and integrate it with chromatin accessibility and DNA methylation to generate a multimodal atlas of ∼400,000 haematopoietic cells from disomic and trisomy 21 (T21) human fetal liver. Chromatin contacts frequently preceded lineage-specific transcription or persisted after transcription declined, revealing 3D chromatin priming and memory. Unexpectedly, B-lineage and erythroid differentiation followed opposing architectural trajectories, with progressive loss and gain of chromatin connectivity, respectively. T21 disproportionately disrupted B-lineage architecture, redistributed interactions towards shorter genomic distances and weakened an EBF1-centred regulatory circuit. Deletion of a T21-sensitive EBF1 loop anchor reproduced the CLP-to-B-progenitor bottleneck observed in T21. These findings establish 3D genome architecture as an organizing layer of human fetal haematopoiesis that links developmental potential with lineage-specific vulnerability to genomic perturbation.
A ∼400,000-cell multimodal atlas resolves human fetal haematopoietic genome regulation3D chromatin encodes developmental priming and persistenceTrisomy 21 selectively disrupts B-lineage genome architecture A T21-sensitive EBF1 loop is required for normal B-cell development.
PMID:
42926741
Bibliographic data and abstract were imported from PubMed on 25 Oct 2026.
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