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<p>Erythropoiesis is a tightly regulated process involving rapid cell proliferation with orderly differentiation to ensure production of millions of RBCs. TGF-β1 is a key regulator of erythropoiesis, however, the mechanisms via which it regulates erythropoiesis are not well elucidated. Using myelodysplastic syndromes patient samples, we show that elevated TGF-β1 and SMAD2 signaling correlates with the degree of anemia. Functional studies in primary human HSPCs demonstrate that TGF-β1 exerts a bifurcated effect — suppressing proliferation and inducing premature erythroid differentiation — both of which are rescued by clinical-stage TGFBR1 inhibitor. Through integrative RNA-seq, ChIP-seq, and Micro-C analyses, we find TGF-β1 activates β-globin LCR, driving early differentiation, while concurrently disrupting the MYC enhancer–promoter interaction to block proliferation. We validate erythropoiesis defects in vivo by performing single-cell RNA-seq in a TGF-β1 overexpressing mouse model. Overall, we show that TGF-β1/SMAD2 signaling re-wires chromatin to regulate erythropoiesis by affecting the β-LCR and MYC super enhancer regions.</p>

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Chromatin rewiring of β-globin and MYC enhancers by TGF-β1 drives defective erythropoiesis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月13日

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  • Srinivas Aluri,
  • Kimo Bachiashvili,
  • Anjali Budhathoki,
  • Jong Jin Jeong,
  • Shanisha Gordon-Mitchell,
  • Samarpana Chakraborty,
  • Jung-In Yang,
  • Srabani Sahu,
  • Sanjay Pandey,
  • Micheal Sandhu,
  • Mahinder Paul,
  • Wenjun Deng,
  • Rahul Sanawar,
  • Plabani Sahu,
  • Leah Kravets,
  • Sarah Aminov,
  • Ritesh Aggarwal,
  • Beamon Agarwal,
  • Divij Verma,
  • Gaurav S. Choudhary,
  • Tushar D. Bhagat,
  • Milagros Carbajal,
  • Rongbao Zhao,
  • Kith Pradhan,
  • Shahina Maqbool,
  • Seong-Jin Kim,
  • Ulrich G. Steidl,
  • Aditi Shastri,
  • Marc Raaijmakers,
  • Andrea Pellagatti,
  • Jacqueline Boultwood,
  • Amittha Wickrema,
  • Amit Verma

摘要

Erythropoiesis is a tightly regulated process involving rapid cell proliferation with orderly differentiation to ensure production of millions of RBCs. TGF-β1 is a key regulator of erythropoiesis, however, the mechanisms via which it regulates erythropoiesis are not well elucidated. Using myelodysplastic syndromes patient samples, we show that elevated TGF-β1 and SMAD2 signaling correlates with the degree of anemia. Functional studies in primary human HSPCs demonstrate that TGF-β1 exerts a bifurcated effect — suppressing proliferation and inducing premature erythroid differentiation — both of which are rescued by clinical-stage TGFBR1 inhibitor. Through integrative RNA-seq, ChIP-seq, and Micro-C analyses, we find TGF-β1 activates β-globin LCR, driving early differentiation, while concurrently disrupting the MYC enhancer–promoter interaction to block proliferation. We validate erythropoiesis defects in vivo by performing single-cell RNA-seq in a TGF-β1 overexpressing mouse model. Overall, we show that TGF-β1/SMAD2 signaling re-wires chromatin to regulate erythropoiesis by affecting the β-LCR and MYC super enhancer regions.