The multi-lineage transcription factor ISL1 controls cardiomyocyte cell fate through interaction with NKX2.5.

Autor:	Maven BEJ; Gladstone Institutes, San Francisco, CA, USA; Developmental and Stem Cell Biology PhD Program, University of California, San Francisco, San Francisco, CA, USA; Roddenberry Center for Stem Cell Biology at Gladstone, San Francisco, CA, USA., Gifford CA; Gladstone Institutes, San Francisco, CA, USA; Roddenberry Center for Stem Cell Biology at Gladstone, San Francisco, CA, USA., Weilert M; Stowers Institute for Medical Research, Kansas City, MO, USA., Gonzalez-Teran B; Gladstone Institutes, San Francisco, CA, USA; Roddenberry Center for Stem Cell Biology at Gladstone, San Francisco, CA, USA., Hüttenhain R; Gladstone Institutes, San Francisco, CA, USA; Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, CA, USA; Quantitative Biosciences Institute (QBI), University of California San Francisco, San Francisco, San Francisco, CA, USA., Pelonero A; Gladstone Institutes, San Francisco, CA, USA; Roddenberry Center for Stem Cell Biology at Gladstone, San Francisco, CA, USA., Ivey KN; Gladstone Institutes, San Francisco, CA, USA; Roddenberry Center for Stem Cell Biology at Gladstone, San Francisco, CA, USA., Samse-Knapp K; Gladstone Institutes, San Francisco, CA, USA; Roddenberry Center for Stem Cell Biology at Gladstone, San Francisco, CA, USA., Kwong W; Gladstone Institutes, San Francisco, CA, USA; Roddenberry Center for Stem Cell Biology at Gladstone, San Francisco, CA, USA., Gordon D; Gladstone Institutes, San Francisco, CA, USA; Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, CA, USA; Quantitative Biosciences Institute (QBI), University of California San Francisco, San Francisco, San Francisco, CA, USA., McGregor M; Gladstone Institutes, San Francisco, CA, USA; Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, CA, USA; Quantitative Biosciences Institute (QBI), University of California San Francisco, San Francisco, San Francisco, CA, USA., Nishino T; Gladstone Institutes, San Francisco, CA, USA; Roddenberry Center for Stem Cell Biology at Gladstone, San Francisco, CA, USA., Okorie E; Gladstone Institutes, San Francisco, CA, USA; Roddenberry Center for Stem Cell Biology at Gladstone, San Francisco, CA, USA., Rossman S; Gladstone Institutes, San Francisco, CA, USA; Roddenberry Center for Stem Cell Biology at Gladstone, San Francisco, CA, USA., Costa MW; Gladstone Institutes, San Francisco, CA, USA; Roddenberry Center for Stem Cell Biology at Gladstone, San Francisco, CA, USA., Krogan NJ; Gladstone Institutes, San Francisco, CA, USA; Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, CA, USA; Quantitative Biosciences Institute (QBI), University of California San Francisco, San Francisco, San Francisco, CA, USA., Zeitlinger J; Stowers Institute for Medical Research, Kansas City, MO, USA; Department of Pathology and Laboratory Medicine, University of Kansas School of Medicine, Kansas City, KS, USA., Srivastava D; Gladstone Institutes, San Francisco, CA, USA; Roddenberry Center for Stem Cell Biology at Gladstone, San Francisco, CA, USA; Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA, USA; Department of Pediatrics, UCSF School of Medicine, San Francisco, CA, USA. Electronic address: deepak.srivastava@gladstone.ucsf.edu.
Jazyk:	angličtina
Zdroj:	Stem cell reports [Stem Cell Reports] 2023 Nov 14; Vol. 18 (11), pp. 2138-2153. Date of Electronic Publication: 2023 Oct 19.
DOI:	10.1016/j.stemcr.2023.09.014
Abstrakt:	Congenital heart disease often arises from perturbations of transcription factors (TFs) that guide cardiac development. ISLET1 (ISL1) is a TF that influences early cardiac cell fate, as well as differentiation of other cell types including motor neuron progenitors (MNPs) and pancreatic islet cells. While lineage specificity of ISL1 function is likely achieved through combinatorial interactions, its essential cardiac interacting partners are unknown. By assaying ISL1 genomic occupancy in human induced pluripotent stem cell-derived cardiac progenitors (CPs) or MNPs and leveraging the deep learning approach BPNet, we identified motifs of other TFs that predicted ISL1 occupancy in each lineage, with NKX2.5 and GATA motifs being most closely associated to ISL1 in CPs. Experimentally, nearly two-thirds of ISL1-bound loci were co-occupied by NKX2.5 and/or GATA4. Removal of NKX2.5 from CPs led to widespread ISL1 redistribution, and overexpression of NKX2.5 in MNPs led to ISL1 occupancy of CP-specific loci. These results reveal how ISL1 guides lineage choices through a combinatorial code that dictates genomic occupancy and transcription. Competing Interests: Declaration of interests D.S. is a co-founder and member of the board of directors of Tenaya Therapeutics and has equity in Tenaya Therapeutics. K.N.I. is an employee and shareholder of Tenaya Therapeutics. N.J.K. has received research support from Vir Biotechnology, F. Hoffmann-La Roche, and Rezo Therapeutics. N.J.K. has financially compensated consulting agreements with Maze Therapeutics, Interline Therapeutics, Rezo Therapeutics, and GEn1E Lifesciences, Inc. He is on the Board of Directors of Rezo Therapeutics and is a shareholder in Tenaya Therapeutics, Maze Therapeutics, Rezo Therapeutics, and Interline Therapeutics. (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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