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. 2023 Jan 19;55(2):232–245. doi: 10.1038/s41588-022-01280-z

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© The Author(s) 2023

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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Extended Data Fig. 1 — a. NOTCH1 is composed of an extracellular domain (NEC) and a transmembrane and cytoplasmic unit (NTM). Domains of NOTCH1 are indicated, arrows show epitopes recognized by anti-NOTCH1 (blue) and anti-NICD1 (orange) antibodies. Ligand binding results in proteolytic cleavages, after which the intracellular domain (NICD) migrates to the nucleus and activates transcription. Domains: EGF, epidermal growth factor like repeats, LNR, Lin12/Notch repeats, HD, heterodimerization, TM, transmembrane, RAM, RBP-J associated module, ANK, ankyrin repeats, TAD, trans-activation domain, PEST, rich in proline, glutamate, serine, and threonine, NRR, negative regulatory region. b. Human esophageal epithelium. Proliferation is confined to the lower layers. Differentiating cells migrate to tissue surface. Pa, papillae. Protein expression shown on right. c. Representative section stained for NOTCH1 (red) and DNA (blue) showing subset of results in Fig. 1b for donor PD31008. Left: sample identification (Id), NOTCH1 staining status (+ or −). Right: non-synonymous NOTCH1 mutations, variant allele frequency (VAF) and copy neutral loss of heterozygosity (CNLOH) if detected, with B allele frequency (BAF) value. Mutation effects: Indel_Splicing, gray; Missense, blue; Nonsense, red. Dashed lines delineate epithelium and submucosa (white) and borders of sequenced samples (yellow). Scale bar, 250 µm. d. Copy number calls for samples PD31008bc and bd, shown in c, Fig. 1d–f and Supplementary table 4. Left plot, analysis of total copy number along chromosome 9 for samples bc and bd. Middle, right plots, BAF along chromosome 9 and NOTCH1 locus, respectively. Red lines denote significant difference from control, black lines indicate no significant difference. e. Successive sections of esophagus from older donors stained for NICD1, Ki67 and Hematoxylin and eosin (H&E). Images representative of 4 donors. Scale bars, 100 µm. f, g, h. Tissue thickness (f), cell density (g) and proportion of proliferative cells (h) in NICD1 positive and negative areas. Each dot represents a donor. For f, NICD1+, n = 14 areas from 4 donors, NICD1−, n = 15 areas from 4 donors. For g, NICD1+: 10795 cells from 4 donors, NICD1−: 11593 cells form 4 donors. For h, NICD1+: 5402 cells from 4 donors, NICD1−: 6204 cells from 4 donors. Two-tailed paired t-test. See Supplementary Tables 1–5.