Chromatin rewiring of β-globin and MYC enhancers by TGF-β1 drives defective erythropoiesis.
Publication/Presentation Date
5-13-2026
Abstract
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.
ISSN
2041-1723
Published In/Presented At
Aluri S, Bachiashvili K, Budhathoki A, Jeong JJ, Gordon-Mitchell S, Chakraborty S, Yang JI, Sahu S, Pandey S, Sandhu M, Paul M, Deng W, Sanawar R, Sahu P, Kravets L, Aminov S, Aggarwal R, Agarwal B, Verma D, Choudhary GS, Bhagat TD, Carbajal M, Zhao R, Pradhan K, Maqbool S, Kim SJ, Steidl UG, Shastri A, Raaijmakers M, Pellagatti A, Boultwood J, Wickrema A, Verma A. Chromatin rewiring of β-globin and MYC enhancers by TGF-β1 drives defective erythropoiesis. Nat Commun. 2026 May 13. doi: 10.1038/s41467-026-72963-y. Epub ahead of print. PMID: 42129196.
Disciplines
Medicine and Health Sciences
PubMedID
42129196
Department(s)
Department of Pathology and Laboratory Medicine
Document Type
Article