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
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
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Research Article Development Hematology

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

Abstract

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 BM remain incompletely understood. Here, we identify the mammalian Polycomb Group 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 KO 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.

Authors

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

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Figure 2

Loss of Yy1 leads to reduction of HSC and progenitor populations in FL.

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Loss of Yy1 leads to reduction of HSC and progenitor populations in FL. ...
All Yy1fl/fl Vav-Cre and Vav-Cre fetuses were evaluated at E14.5 of fetal development. (A) Representative gross pictures; histopathology pictures of fetuses and FLs. (B) Total FL cell numbers. (C) Red blood cell flow analysis and (D) quantification. (E) Representative flow gating strategy for HSC (Lin–CD41–CD48–Mac1+CD150+cKit+Sca1+) and MPP (Lin–CD41–CD48–Mac1+CD150–cKit+Sca1+). (F) Quantification of percentage and absolute cell numbers of HSC and MPP. (G) Quantification of LSK (Lin–cKit+Sca1+), MP (Lin–cKit+Sca1–), common myeloid progenitors (Lin–cKit+Sca1–CD34+Fclo), granulocyte-monocyte progenitors (Lin–cKit+Sca1–CD34+Fchi), and megakaryocyte-erythroid progenitors (Lin–cKit+Sca1–CD34–Fclo). (H) Colony formation assays from total FL cells. (I) Representative gating strategies for the Ki67/DAPI proliferation assay. E14.5 HSC cells were gated for G0 (Ki67–DAPI–), G1 (Ki67+DAPI–), and S/G2/M (Ki67+DAPI+) phases. (J) Quantification of percentage of fetal HSC, MPP, LSK, and MP cells in G0, G1, and S/G2/M phases. (K) Representative flow gating and quantification of intracellular ROS level in fetal HSCs (Lin–CD41–CD48–Mac1+CD150+cKit+Sca1+). (L) Seahorse assay to detect OCR in Yy1+/+ and Yy1–/– FL LK cells. OCR was measured at baseline and after sequential treatment with oligomycin, FCCP, and rotenone/antimycin A. Number of fetuses = n; graphs show mean ± SD, *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001, by unpaired 2-tailed t test (B, D, F, G, H, K, and L) and 2-way ANOVA (G and J).