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Wang Y, Li W, Schulz VP, et al. Impairment of human terminal erythroid differentiation by histone deacetylase 5 deficiency. Blood. 2021;138(17):1615-1627doi: 10.1182/blood.2020007401.
Wang, Y., Li, W., Schulz, V. P., Zhao, H., Qu, X., Qi, Q., Cheng, Y., Guo, X., Zhang, S., Wei, X., Liu, D., Yazdanbakhsh, K., Hillyer, C. D., Mohandas, N., Chen, L., Gallagher, P. G., & An, X. (2021). Impairment of human terminal erythroid differentiation by histone deacetylase 5 deficiency. Blood, 138(17), 1615-1627. https://doi.org/10.1182/blood.2020007401
Wang, Yaomei, et al. "Impairment of human terminal erythroid differentiation by histone deacetylase 5 deficiency." Blood vol. 138,17 (2021): 1615-1627. doi: https://doi.org/10.1182/blood.2020007401
Wang Y, Li W, Schulz VP, Zhao H, Qu X, Qi Q, Cheng Y, Guo X, Zhang S, Wei X, Liu D, Yazdanbakhsh K, Hillyer CD, Mohandas N, Chen L, Gallagher PG, An X. Impairment of human terminal erythroid differentiation by histone deacetylase 5 deficiency. Blood. 2021 Oct 28;138(17):1615-1627. doi: 10.1182/blood.2020007401. PMID: 34036344; PMCID: PMC8554652.
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Blood. 2021 Oct 28;138(17):1615-1627. doi: 10.1182/blood.2020007401.

Impairment of human terminal erythroid differentiation by histone deacetylase 5 deficiency.

Blood

Yaomei Wang, Wei Li, Vincent P Schulz, Huizhi Zhao, Xiaoli Qu, Qian Qi, Yong Cheng, Xinhua Guo, Shijie Zhang, Xin Wei, Donghao Liu, Karina Yazdanbakhsh, Christopher D Hillyer, Narla Mohandas, Lixiang Chen, Patrick G Gallagher, Xiuli An

Affiliations

  1. School of Life Sciences, Zhengzhou University, Zhengzhou, China.
  2. Laboratory of Membrane Biology, New York Blood Center, New York, NY.
  3. Department of Hematology, the Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China.
  4. Department of Hematology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
  5. Department of Pediatrics, Yale University, New Haven, CT.
  6. Department of Hematology, St. Jude Children's Research Hospital, Memphis, TN.
  7. Department of Anesthesiology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
  8. Laboratory of Complement Biology and.
  9. Red Cell Physiology Laboratory, New York Blood Center, New York, NY; and.
  10. Department of Pathology and.
  11. Department of Genetics, Yale University, New Haven, CT.

PMID: 34036344 PMCID: PMC8554652 DOI: 10.1182/blood.2020007401

Abstract

Histone deacetylases (HDACs) are a group of enzymes that catalyze the removal of acetyl groups from histone and nonhistone proteins. HDACs have been shown to have diverse functions in a wide range of biological processes. However, their roles in mammalian erythropoiesis remain to be fully defined. This study showed that, of the 11 classic HDAC family members, 6 (HDAC1, -2, -3, and HDAC5, -6, -7) are expressed in human erythroid cells, with HDAC5 most significantly upregulated during terminal erythroid differentiation. Knockdown of HDAC5 by either short hairpin RNA or small interfering RNA in human CD34+ cells followed by erythroid cell culture led to increased apoptosis, decreased chromatin condensation, and impaired enucleation of erythroblasts. Biochemical analyses revealed that HDAC5 deficiency resulted in activation of p53 in association with increased acetylation of p53. Furthermore, although acetylation of histone 4 (H4) is decreased during normal terminal erythroid differentiation, HDAC5 deficiency led to increased acetylation of H4 (K12) in late-stage erythroblasts. This increased acetylation was accompanied by decreased chromatin condensation, implying a role for H4 (K12) deacetylation in chromatin condensation. ATAC-seq and RNA sequencing analyses revealed that HDAC5 knockdown leads to increased chromatin accessibility genome-wide and global changes in gene expression. Moreover, pharmacological inhibition of HDAC5 by the inhibitor LMK235 also led to increased H4 acetylation, impaired chromatin condensation, and enucleation. Taken together, our findings have uncovered previously unrecognized roles and molecular mechanisms of action for HDAC5 in human erythropoiesis. These results may provide insights into understanding the anemia associated with HDAC inhibitor treatment.

© 2021 by The American Society of Hematology.

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