Disrupted chromatin architecture blocks B lymphopoiesis in Down syndrome

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.

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BibTeX RIS

BibTeX

@misc{liao2026disrupted,
  title = {{Disrupted chromatin architecture blocks B lymphopoiesis in Down syndrome}},
  author = {Z. Liao and M. Zhang and B. Y. Soong and B. Zhu and L. L. Boshans and K. Wang and M. Quijada-Alamo and I. Osakwe and Z. Wang and P. Fiore and D. Hasson and E. Wagenblast and S. Ma},
  howpublished = {bioRxiv},
  year = {2026},
  month = oct,
  doi = {10.64898/2026.10.07.757425},
  url = {https://www.biorxiv.org/content/10.64898/2026.10.07.757425v1},
  note = {CC BY-NC-ND},
}

RIS

TY  - UNPB
TI  - Disrupted chromatin architecture blocks B lymphopoiesis in Down syndrome
AU  - Z. Liao
AU  - M. Zhang
AU  - B. Y. Soong
AU  - B. Zhu
AU  - L. L. Boshans
AU  - K. Wang
AU  - M. Quijada-Alamo
AU  - I. Osakwe
AU  - Z. Wang
AU  - P. Fiore
AU  - D. Hasson
AU  - E. Wagenblast
AU  - S. Ma
PY  - 2026
DA  - 2026/10/07
PB  - bioRxiv
DO  - 10.64898/2026.10.07.757425
UR  - https://www.biorxiv.org/content/10.64898/2026.10.07.757425v1
AB  - 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.
ER  -

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