Carrelha, J. et al. Hierarchically related lineage-restricted fates of multipotent haematopoietic stem cells. Nature 554, 106–111 (2018).
Banjac, I. et al. Fate mapping in mouse demonstrates early secretory differentiation directly from Lgr5+ intestinal stem cells. Dev. Cell 60, 1281–1289 (2025).
Ohlstein, B. & Spradling, A. The adult Drosophila posterior midgut is maintained by pluripotent stem cells. Nature 439, 470–474 (2006).
Micchelli, C. A. & Perrimon, N. Evidence that stem cells reside in the adult Drosophila midgut epithelium. Nature 439, 475–479 (2006).
Ohlstein, B. & Spradling, A. Multipotent Drosophila intestinal stem cells specify daughter cell fates by differential Notch signaling. Science 315, 988–992 (2007).
Amcheslavsky, A., Jiang, J. & Ip, Y. T. Tissue damage-induced intestinal stem cell division in Drosophila. Cell Stem Cell 4, 49–61 (2009).
Salle, J. et al. Intrinsic regulation of enteroendocrine fate by Numb. EMBO J. 36, 1928–1945 (2017).
Gao, P. et al. Deterministic progenitor behavior and unitary production of neurons in the neocortex. Cell 159, 775–788 (2014).
Beumer, J. & Clevers, H. Cell fate specification and differentiation in the adult mammalian intestine. Nat. Rev. Mol. Cell Biol. 22, 39–53 (2021).
Jiang, H. et al. Cytokine/Jak/Stat signaling mediates regeneration and homeostasis in the Drosophila midgut. Cell 137, 1343–1355 (2009).
Biteau, B., Hochmuth, C. E. & Jasper, H. Maintaining tissue homeostasis: dynamic control of somatic stem cell activity. Cell Stem Cell 9, 402–411 (2011).
Josserand, M. et al. Chromatin state transitions in the Drosophila intestinal lineage identify principles of cell-type specification. Dev. Cell 58, 3048–3063 (2023).
Zhang, S. et al. Eclosion muscles secrete ecdysteroids to initiate asymmetric intestinal stem cell division in Drosophila. Dev. Cell 59, 125–140 (2024).
Wu, S. et al. Apical–basal polarity precisely determines intestinal stem cell number by regulating Prospero threshold. Cell Rep. 42, 112093 (2023).
Guo, Z. & Ohlstein, B. Stem cell regulation. bidirectional Notch signaling regulates Drosophila intestinal stem cell multipotency. Science 350, aab0988 (2015).
Chen, J. et al. Transient Scute activation via a self-stimulatory loop directs enteroendocrine cell pair specification from self-renewing intestinal stem cells. Nat. Cell Biol. 20, 152–161 (2018).
Zeng, X. & Hou, S. X. Enteroendocrine cells are generated from stem cells through a distinct progenitor in the adult Drosophila posterior midgut. Development 142, 644–653 (2015).
Beehler-Evans, R. & Micchelli, C. A. Generation of enteroendocrine cell diversity in midgut stem cell lineages. Development 142, 654–664 (2015).
Bardin, A. J., Perdigoto, C. N., Southall, T. D., Brand, A. H. & Schweisguth, F. Transcriptional control of stem cell maintenance in the Drosophila intestine. Development 137, 705–714 (2010).
Antonello, Z. A., Reiff, T., Ballesta-Illan, E. & Dominguez, M. Robust intestinal homeostasis relies on cellular plasticity in enteroblasts mediated by miR-8–Escargot switch. EMBO J. 34, 2025–2041 (2015).
Buchon, N. et al. Morphological and molecular characterization of adult midgut compartmentalization in Drosophila. Cell Rep. 3, 1725–1738 (2013).
Biteau, B. & Jasper, H. Slit/Robo signaling regulates cell fate decisions in the intestinal stem cell lineage of Drosophila. Cell Rep. 7, 1867–1875 (2014).
Liang, J., Balachandra, S., Ngo, S. & O’Brien, L. E. Feedback regulation of steady-state epithelial turnover and organ size. Nature 548, 588–591 (2017).
O’Brien, L. E., Soliman, S. S., Li, X. & Bilder, D. Altered modes of stem cell division drive adaptive intestinal growth. Cell 147, 603–614 (2011).
Guo, Z., Driver, I. & Ohlstein, B. Injury-induced BMP signaling negatively regulates Drosophila midgut homeostasis. J. Cell Biol. 201, 945–961 (2013).
Lee, T. & Luo, L. Mosaic analysis with a repressible cell marker for studies of gene function in neuronal morphogenesis. Neuron 22, 451–461 (1999).
de Navascues, J. et al. Drosophila midgut homeostasis involves neutral competition between symmetrically dividing intestinal stem cells. EMBO J. 31, 2473–2485 (2012).
Snippert, H. J. et al. Intestinal crypt homeostasis results from neutral competition between symmetrically dividing Lgr5 stem cells. Cell 143, 134–144 (2010).
Simons, B. D. & Clevers, H. Strategies for homeostatic stem cell self-renewal in adult tissues. Cell 145, 851–862 (2011).
Reiff, T. et al. Notch and EGFR regulate apoptosis in progenitor cells to ensure gut homeostasis in Drosophila. EMBO J. 38, e101346 (2019).
Lopez-Garcia, C., Klein, A. M., Simons, B. D. & Winton, D. J. Intestinal stem cell replacement follows a pattern of neutral drift. Science 330, 822–825 (2010).
Biteau, B., Hochmuth, C. E. & Jasper, H. JNK activity in somatic stem cells causes loss of tissue homeostasis in the aging Drosophila gut. Cell Stem Cell 3, 442–455 (2008).
Buchon, N., Broderick, N. A., Poidevin, M., Pradervand, S. & Lemaitre, B. Drosophila intestinal response to bacterial infection: activation of host defense and stem cell proliferation. Cell Host Microbe 5, 200–211 (2009).
Schuettengruber, B., Bourbon, H. M., Di Croce, L. & Cavalli, G. Genome regulation by Polycomb and Trithorax: 70 years and counting. Cell 171, 34–57 (2017).
Steffen, P. A. & Ringrose, L. What are memories made of? How Polycomb and Trithorax proteins mediate epigenetic memory. Nat. Rev. Mol. Cell Biol. 15, 340–356 (2014).
Tauc, H. M. et al. Age-related changes in polycomb gene regulation disrupt lineage fidelity in intestinal stem cells. eLife 10, e62250 (2021).
Brand, M., Nakka, K., Zhu, J. & Dilworth, F. J. Polycomb/Trithorax antagonism: cellular memory in stem cell fate and function. Cell Stem Cell 24, 518–533 (2019).
Veneti, Z. et al. Polycomb-mediated silencing of miR-8 is required for maintenance of intestinal stemness in Drosophila melanogaster. Nat. Commun. 15, 1924 (2024).
Schmitges, F. W. et al. Histone methylation by PRC2 is inhibited by active chromatin marks. Mol. Cell 42, 330–341 (2011).
Tie, F. et al. CBP-mediated acetylation of histone H3 lysine 27 antagonizes Drosophila Polycomb silencing. Development 136, 3131–3141 (2009).
McKay, D. J. et al. Interrogating the function of metazoan histones using engineered gene clusters. Dev. Cell 32, 373–386 (2015).
Zhang, W. et al. Probing the function of metazoan histones with a systematic library of H3 and H4 Mutants. Dev. Cell 48, 406–419 (2019).
Gunesdogan, U., Jackle, H. & Herzig, A. A genetic system to assess in vivo the functions of histones and histone modifications in higher eukaryotes. EMBO Rep. 11, 772–776 (2010).
Coleman, R. T. & Struhl, G. Causal role for inheritance of H3K27me3 in maintaining the OFF state of a Drosophila HOX gene. Science 356, eaai8236 (2017).
Liefke, R. et al. Histone demethylase KDM5A is an integral part of the core Notch–RBP-J repressor complex. Genes Dev. 24, 590–601 (2010).
Schwanbeck, R. The role of epigenetic mechanisms in Notch signaling during development. J. Cell. Physiol. 230, 969–981 (2015).
Guenin, L. et al. Spatio-temporal expression of Prospero is finely tuned to allow the correct development and function of the nervous system in Drosophila melanogaster. Dev. Biol. 304, 62–74 (2007).
Zeng, X., Chauhan, C. & Hou, S. X. Characterization of midgut stem cell- and enteroblast-specific Gal4 lines in Drosophila. Genesis 48, 607–611 (2010).
Kaya-Okur, H. S. et al. CUT&Tag for efficient epigenomic profiling of small samples and single cells. Nat. Commun. 10, 1930 (2019).
Li, Z. et al. A switch in tissue stem cell identity causes neuroendocrine tumors in Drosophila gut. Cell Rep. 30, 1724–1734 (2020).
Wang, C., Guo, X., Dou, K., Chen, H. & Xi, R. Ttk69 acts as a master repressor of enteroendocrine cell specification in Drosophila intestinal stem cell lineages. Development 142, 3321–3331 (2015).
Yin, C. & Xi, R. A phyllopod-mediated feedback loop promotes intestinal stem cell enteroendocrine commitment in Drosophila. Stem Cell Rep. 10, 43–57 (2018).
Reinberg, D. & Vales, L. D. Chromatin domains rich in inheritance. Science 361, 33–34 (2018).
Obniski, R., Sieber, M. & Spradling, A. C. Dietary lipids modulate Notch signaling and influence adult intestinal development and metabolism in Drosophila. Dev. Cell 47, 98–111 (2018).
Yu, Z. et al. Nutrient-sensing alteration leads to age-associated distortion of intestinal stem cell differentiating direction. Nat. Commun. 15, 9243 (2024).
He, L., Si, G., Huang, J., Samuel, A. D. T. & Perrimon, N. Mechanical regulation of stem-cell differentiation by the stretch-activated Piezo channel. Nature 555, 103–106 (2018).
Gao, J. et al. Dietary l-Glu sensing by enteroendocrine cells adjusts food intake via modulating gut PYY/NPF secretion. Nat. Commun. 15, 3514 (2024).
Lin, H.-H. et al. A nutrient-specific gut hormone arbitrates between courtship and feeding. Nature 602, 632–638 (2022).
Vo, L. T. et al. Regulation of embryonic haematopoietic multipotency by EZH1. Nature 553, 506–510 (2018).
Meng, Y. & Nerlov, C. Epigenetic regulation of hematopoietic stem cell fate. Trends Cell Biol. 35, 217–229 (2025).
Holsopple, J. M., Cook, K. R. & Popodi, E. M. Enteroendocrine cell expression of split-GAL4 drivers bearing regulatory sequences associated with panneuronally expressed genes in Drosophila melanogaster. MicroPubl. Biol. https://doi.org/10.17912/micropub.biology.000628 (2022).
Hay, B. A., Wolff, T. & Rubin, G. M. Expression of baculovirus P35 prevents cell death in Drosophila. Development 120, 2121–2129 (1994).
Hay, B. A., Wassarman, D. A. & Rubin, G. M. Drosophila homologs of baculovirus inhibitor of apoptosis proteins function to block cell death. Cell 83, 1253–1262 (1995).
Kidd, S., Lieber, T. & Young, M. W. Ligand-induced cleavage and regulation of nuclear entry of Notch in Drosophila melanogaster embryos. Genes Dev. 12, 3728–3740 (1998).
Harrison, D. A. & Perrimon, N. Simple and efficient generation of marked clones in Drosophila. Curr. Biol. 3, 424–433 (1993).
Ohno, K., McCabe, D., Czermin, B., Imhof, A. & Pirrotta, V. ESC, ESCL and their roles in Polycomb group mechanisms. Mech. Dev. 125, 527–541 (2008).
Dura, J. M. et al. A complex genetic locus, polyhomeotic, is required for segmental specification and epidermal development in D. melanogaster. Cell 51, 829–839 (1987).
Guo, X. et al. The cellular diversity and transcription factor code of Drosophila enteroendocrine cells. Cell Rep. 29, 4172–4185 (2019).
Guo, Z., Han, Y., Jiang, Q. & Dong, T. Code for regional fitting the symmetric division ratio. Figshare https://doi.org/10.6084/m9.figshare.31311136 (2026).
Guo, Z., Jiang, Q., Han, Y. & Dong, T. Code for EEC proportion simulation. Figshare https://doi.org/10.6084/m9.figshare.31311127 (2026).
Guo, Z. CUT_Tag codes and files. Figshare https://doi.org/10.6084/m9.figshare.29569391 (2025).
Guo, Z., Yuan, Q. & Dong, T. R code for data visualization. Figshare https://doi.org/10.6084/m9.figshare.32617422 (2026).

