Chromatin factor YY1 controls fetal hematopoietic stem cell migration and engraftment in mice

Sahitya Saka; Zhanping Lu; Yinghua Wang; Peng Liu; Deependra K. Singh; Junki P. Lee; Carmen G. Palii; Tyler R. Alvarez; Anna L. F. V. Assumpção; Xiaona You; Jing Zhang; Marjorie Brand; Michael L. Atchison; Xuan Pan

doi:10.1172/JCI188140

¹Department of Medical Sciences, University of Wisconsin, Madison, United States of America

²Carbone Cancer Center, University of Wisconsin, Madison, United States of America

³Department of Biomedical Sciences, University of Pennsylvania, Philadelphia, United States of America

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¹Department of Medical Sciences, University of Wisconsin, Madison, United States of America

²Carbone Cancer Center, University of Wisconsin, Madison, United States of America

³Department of Biomedical Sciences, University of Pennsylvania, Philadelphia, United States of America

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¹Department of Medical Sciences, University of Wisconsin, Madison, United States of America

²Carbone Cancer Center, University of Wisconsin, Madison, United States of America

³Department of Biomedical Sciences, University of Pennsylvania, Philadelphia, United States of America

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¹Department of Medical Sciences, University of Wisconsin, Madison, United States of America

²Carbone Cancer Center, University of Wisconsin, Madison, United States of America

³Department of Biomedical Sciences, University of Pennsylvania, Philadelphia, United States of America

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¹Department of Medical Sciences, University of Wisconsin, Madison, United States of America

²Carbone Cancer Center, University of Wisconsin, Madison, United States of America

³Department of Biomedical Sciences, University of Pennsylvania, Philadelphia, United States of America

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¹Department of Medical Sciences, University of Wisconsin, Madison, United States of America

²Carbone Cancer Center, University of Wisconsin, Madison, United States of America

³Department of Biomedical Sciences, University of Pennsylvania, Philadelphia, United States of America

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¹Department of Medical Sciences, University of Wisconsin, Madison, United States of America

²Carbone Cancer Center, University of Wisconsin, Madison, United States of America

³Department of Biomedical Sciences, University of Pennsylvania, Philadelphia, United States of America

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¹Department of Medical Sciences, University of Wisconsin, Madison, United States of America

²Carbone Cancer Center, University of Wisconsin, Madison, United States of America

³Department of Biomedical Sciences, University of Pennsylvania, Philadelphia, United States of America

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¹Department of Medical Sciences, University of Wisconsin, Madison, United States of America

²Carbone Cancer Center, University of Wisconsin, Madison, United States of America

³Department of Biomedical Sciences, University of Pennsylvania, Philadelphia, United States of America

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¹Department of Medical Sciences, University of Wisconsin, Madison, United States of America

²Carbone Cancer Center, University of Wisconsin, Madison, United States of America

³Department of Biomedical Sciences, University of Pennsylvania, Philadelphia, United States of America

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¹Department of Medical Sciences, University of Wisconsin, Madison, United States of America

²Carbone Cancer Center, University of Wisconsin, Madison, United States of America

³Department of Biomedical Sciences, University of Pennsylvania, Philadelphia, United States of America

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¹Department of Medical Sciences, University of Wisconsin, Madison, United States of America

²Carbone Cancer Center, University of Wisconsin, Madison, United States of America

³Department of Biomedical Sciences, University of Pennsylvania, Philadelphia, United States of America

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¹Department of Medical Sciences, University of Wisconsin, Madison, United States of America

²Carbone Cancer Center, University of Wisconsin, Madison, United States of America

³Department of Biomedical Sciences, University of Pennsylvania, Philadelphia, United States of America

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¹Department of Medical Sciences, University of Wisconsin, Madison, United States of America

²Carbone Cancer Center, University of Wisconsin, Madison, United States of America

³Department of Biomedical Sciences, University of Pennsylvania, Philadelphia, United States of America

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J Clin Invest. https://doi.org/10.1172/JCI188140.
Copyright © 2025, Saka et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

Published July 30, 2025 - Version history

The fetal liver is the primary site of hematopoietic stem cell (HSC) generation during embryonic development. However, the molecular mechanisms governing the transition of hematopoiesis from the fetal liver to the bone marrow (BM) remain incompletely understood. Here, we identify the mammalian Polycomb group (PcG) protein Yin Yang 1 (YY1) as a key regulator of this developmental transition. Conditional deletion of Yy1 in the hematopoietic system during fetal development results in neonatal lethality and depletion of the fetal HSC pool. YY1-deficient fetal HSCs exhibit impaired migration and fail to engraft in the adult BM, thereby losing their ability to reconstitute hematopoiesis. Transcriptomic analysis reveals that Yy1 knockout disrupts genetic networks controlling cell motility and adhesion in fetal hematopoietic stem and progenitor cells (HSPCs). Notably, YY1 does not directly bind the promoters of most dysregulated genes. Instead, it modulates chromatin accessibility at regulatory loci, orchestrating broader epigenetic programs essential for HSPC migration and adhesion. Together, these findings establish YY1 as a critical epigenetic regulator of fetal HSC function and provide a mechanistic framework to further decipher how temporal epigenomic configurations determine HSC fetal-to-adult transition during development.

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Chromatin factor YY1 controls fetal hematopoietic stem cell migration and engraftment in mice

Sahitya Saka,¹ Zhanping Lu,¹ Yinghua Wang,¹ Peng Liu,² Deependra K. Singh,¹ Junki P. Lee,¹ Carmen G. Palii,² Tyler R. Alvarez,¹ Anna L. F. V. Assumpção,¹ Xiaona You,² Jing Zhang,² Marjorie Brand,² Michael L. Atchison,³ and Xuan Pan¹

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Chromatin factor YY1 controls fetal hematopoietic stem cell migration and engraftment in mice

Sahitya Saka,1 Zhanping Lu,1 Yinghua Wang,1 Peng Liu,2 Deependra K. Singh,1 Junki P. Lee,1 Carmen G. Palii,2 Tyler R. Alvarez,1 Anna L. F. V. Assumpção,1 Xiaona You,2 Jing Zhang,2 Marjorie Brand,2 Michael L. Atchison,3 and Xuan Pan1

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Sahitya Saka,¹ Zhanping Lu,¹ Yinghua Wang,¹ Peng Liu,² Deependra K. Singh,¹ Junki P. Lee,¹ Carmen G. Palii,² Tyler R. Alvarez,¹ Anna L. F. V. Assumpção,¹ Xiaona You,² Jing Zhang,² Marjorie Brand,² Michael L. Atchison,³ and Xuan Pan¹