IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v16y2025i1d10.1038_s41467-025-56475-9.html
   My bibliography  Save this article

A mechanism-informed deep neural network enables prioritization of regulators that drive cell state transitions

Author

Listed:
  • Xi Xi

    (Tsinghua University)

  • Jiaqi Li

    (Tsinghua University)

  • Jinmeng Jia

    (Tsinghua University)

  • Qiuchen Meng

    (Tsinghua University)

  • Chen Li

    (Tsinghua University)

  • Xiaowo Wang

    (Tsinghua University)

  • Lei Wei

    (Tsinghua University)

  • Xuegong Zhang

    (Tsinghua University
    Tsinghua University)

Abstract

Cells are regulated at multiple levels, from regulations of individual genes to interactions across multiple genes. Some recent neural network models can connect molecular changes to cellular phenotypes, but their design lacks modeling of regulatory mechanisms, limiting the decoding of regulations behind key cellular events, such as cell state transitions. Here, we present regX, a deep neural network incorporating both gene-level regulation and gene-gene interaction mechanisms, which enables prioritizing potential driver regulators of cell state transitions and providing mechanistic interpretations. Applied to single-cell multi-omics data on type 2 diabetes and hair follicle development, regX reliably prioritizes key transcription factors and candidate cis-regulatory elements that drive cell state transitions. Some regulators reveal potential new therapeutic targets, drug repurposing possibilities, and putative causal single nucleotide polymorphisms. This method to analyze single-cell multi-omics data demonstrates how the interpretable design of neural networks can better decode biological systems.

Suggested Citation

  • Xi Xi & Jiaqi Li & Jinmeng Jia & Qiuchen Meng & Chen Li & Xiaowo Wang & Lei Wei & Xuegong Zhang, 2025. "A mechanism-informed deep neural network enables prioritization of regulators that drive cell state transitions," Nature Communications, Nature, vol. 16(1), pages 1-18, December.
  • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-56475-9
    DOI: 10.1038/s41467-025-56475-9
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-025-56475-9
    File Function: Abstract
    Download Restriction: no

    File URL: https://libkey.io/10.1038/s41467-025-56475-9?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Kenji Kamimoto & Blerta Stringa & Christy M. Hoffmann & Kunal Jindal & Lilianna Solnica-Krezel & Samantha A. Morris, 2023. "Dissecting cell identity via network inference and in silico gene perturbation," Nature, Nature, vol. 614(7949), pages 742-751, February.
    2. Junyue Cao & Malte Spielmann & Xiaojie Qiu & Xingfan Huang & Daniel M. Ibrahim & Andrew J. Hill & Fan Zhang & Stefan Mundlos & Lena Christiansen & Frank J. Steemers & Cole Trapnell & Jay Shendure, 2019. "The single-cell transcriptional landscape of mammalian organogenesis," Nature, Nature, vol. 566(7745), pages 496-502, February.
    3. Sadaf Amin & Brandoch Cook & Ting Zhou & Zaniar Ghazizadeh & Raphael Lis & Tuo Zhang & Mona Khalaj & Miguel Crespo & Manuradhi Perera & Jenny Zhaoying Xiang & Zengrong Zhu & Mark Tomishima & Chengyang, 2018. "Discovery of a drug candidate for GLIS3-associated diabetes," Nature Communications, Nature, vol. 9(1), pages 1-12, December.
    4. Zhana Duren & Wenhui Sophia Lu & Joseph G. Arthur & Preyas Shah & Jingxue Xin & Francesca Meschi & Miranda Lin Li & Corey M. Nemec & Yifeng Yin & Wing Hung Wong, 2021. "Sc-compReg enables the comparison of gene regulatory networks between conditions using single-cell data," Nature Communications, Nature, vol. 12(1), pages 1-13, December.
    5. Haitham A. Elmarakeby & Justin Hwang & Rand Arafeh & Jett Crowdis & Sydney Gang & David Liu & Saud H. AlDubayan & Keyan Salari & Steven Kregel & Camden Richter & Taylor E. Arnoff & Jihye Park & Willia, 2021. "Biologically informed deep neural network for prostate cancer discovery," Nature, Nature, vol. 598(7880), pages 348-352, October.
    6. Avlant Nilsson & Joshua M. Peters & Nikolaos Meimetis & Bryan Bryson & Douglas A. Lauffenburger, 2022. "Artificial neural networks enable genome-scale simulations of intracellular signaling," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Dafina M. Angelova & Aleksandra Tsolova & Malwina Prater & Noura Ballasy & Wendi Bacon & Russell S. Hamilton & Danielle Blackwell & Ziyi Yu & Xin Li & Xin Liu & Myriam Hemberger & D. Stephen Charnock-, 2025. "Single-cell RNA sequencing identifies CXADR as a fate determinant of the placental exchange surface," Nature Communications, Nature, vol. 16(1), pages 1-22, December.
    2. J. McClatchy & R. Strogantsev & E. Wolfe & H. Y. Lin & M. Mohammadhosseini & B. A. Davis & C. Eden & D. Goldman & W. H. Fleming & P. Conley & G. Wu & L. Cimmino & H. Mohammed & A. Agarwal, 2023. "Clonal hematopoiesis related TET2 loss-of-function impedes IL1β-mediated epigenetic reprogramming in hematopoietic stem and progenitor cells," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    3. Ci Fu & Xiang Zhang & Amanda O. Veri & Kali R. Iyer & Emma Lash & Alice Xue & Huijuan Yan & Nicole M. Revie & Cassandra Wong & Zhen-Yuan Lin & Elizabeth J. Polvi & Sean D. Liston & Benjamin VanderSlui, 2021. "Leveraging machine learning essentiality predictions and chemogenomic interactions to identify antifungal targets," Nature Communications, Nature, vol. 12(1), pages 1-18, December.
    4. Sandra Curras-Alonso & Juliette Soulier & Thomas Defard & Christian Weber & Sophie Heinrich & Hugo Laporte & Sophie Leboucher & Sonia Lameiras & Marie Dutreix & Vincent Favaudon & Florian Massip & Tho, 2023. "An interactive murine single-cell atlas of the lung responses to radiation injury," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    5. Seung-Hyun Jung & Byung-Hee Hwang & Sun Shin & Eun-Hye Park & Sin-Hee Park & Chan Woo Kim & Eunmin Kim & Eunho Choo & Ik Jun Choi & Filip K. Swirski & Kiyuk Chang & Yeun-Jun Chung, 2022. "Spatiotemporal dynamics of macrophage heterogeneity and a potential function of Trem2hi macrophages in infarcted hearts," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    6. Hailun Zhu & Sihai Dave Zhao & Alokananda Ray & Yu Zhang & Xin Li, 2022. "A comprehensive temporal patterning gene network in Drosophila medulla neuroblasts revealed by single-cell RNA sequencing," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    7. Luke Simpson & Andrew Strange & Doris Klisch & Sophie Kraunsoe & Takuya Azami & Daniel Goszczynski & Triet Minh & Benjamin Planells & Nadine Holmes & Fei Sang & Sonal Henson & Matthew Loose & Jennifer, 2024. "A single-cell atlas of pig gastrulation as a resource for comparative embryology," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    8. Umji Lee & Yadong Zhang & Yonglin Zhu & Allen Chilun Luo & Liyan Gong & Daniel M. Tremmel & Yunhye Kim & Victoria Sofia Villarreal & Xi Wang & Ruei-Zeng Lin & Miao Cui & Minglin Ma & Ke Yuan & Kai Wan, 2024. "Robust differentiation of human pluripotent stem cells into mural progenitor cells via transient activation of NKX3.1," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    9. Andrea Flesken-Nikitin & Coulter Q. Ralston & Dah-Jiun Fu & Andrea J. Micheli & Daryl J. Phuong & Blaine A. Harlan & Christopher S. Ashe & Amanda P. Armstrong & David W. McKellar & Sangeeta Ghuwalewal, 2024. "Pre-ciliated tubal epithelial cells are prone to initiation of high-grade serous ovarian carcinoma," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    10. Yuma Takano & Jun Suzuki & Kotaro Nomura & Gento Fujii & Junko Zenkoh & Hitomi Kawai & Yuta Kuze & Yukie Kashima & Satoi Nagasawa & Yuka Nakamura & Motohiro Kojima & Katsuya Tsuchihara & Masahide Seki, 2024. "Spatially resolved gene expression profiling of tumor microenvironment reveals key steps of lung adenocarcinoma development," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    11. Qian-Yue Zhang & Xiao-Ping Ye & Zheng Zhou & Chen-Fang Zhu & Rui Li & Ya Fang & Rui-Jia Zhang & Lu Li & Wei Liu & Zheng Wang & Shi-Yang Song & Sang-Yu Lu & Shuang-Xia Zhao & Jian-Nan Lin & Huai-Dong S, 2022. "Lymphocyte infiltration and thyrocyte destruction are driven by stromal and immune cell components in Hashimoto’s thyroiditis," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    12. Hyeon-Jin Kim & Greg Booth & Lauren Saunders & Sanjay Srivatsan & José L. McFaline-Figueroa & Cole Trapnell, 2022. "Nuclear oligo hashing improves differential analysis of single-cell RNA-seq," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    13. Zhengyan Kan & Ji Wen & Vinicius Bonato & Jennifer Webster & Wenjing Yang & Vladimir Ivanov & Kimberly Hyunjung Kim & Whijae Roh & Chaoting Liu & Xinmeng Jasmine Mu & Jennifer Lapira-Miller & Jon Oyer, 2025. "Real-world clinical multi-omics analyses reveal bifurcation of ER-independent and ER-dependent drug resistance to CDK4/6 inhibitors," Nature Communications, Nature, vol. 16(1), pages 1-19, December.
    14. Greg Holmes & Ana S. Gonzalez-Reiche & Madrikha Saturne & Susan M. Motch Perrine & Xianxiao Zhou & Ana C. Borges & Bhavana Shewale & Joan T. Richtsmeier & Bin Zhang & Harm Bakel & Ethylin Wang Jabs, 2021. "Single-cell analysis identifies a key role for Hhip in murine coronal suture development," Nature Communications, Nature, vol. 12(1), pages 1-16, December.
    15. Arezou Rahimi & Luis A. Vale-Silva & Maria Fälth Savitski & Jovan Tanevski & Julio Saez-Rodriguez, 2024. "DOT: a flexible multi-objective optimization framework for transferring features across single-cell and spatial omics," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    16. Caroline Hoffmann & Floriane Noel & Maximilien Grandclaudon & Lucile Massenet-Regad & Paula Michea & Philemon Sirven & Lilith Faucheux & Aurore Surun & Olivier Lantz & Mylene Bohec & Jian Ye & Weihua , 2022. "PD-L1 and ICOSL discriminate human Secretory and Helper dendritic cells in cancer, allergy and autoimmunity," Nature Communications, Nature, vol. 13(1), pages 1-20, December.
    17. Katrin Rabold & Martijn Zoodsma & Inge Grondman & Yunus Kuijpers & Manita Bremmers & Martin Jaeger & Bowen Zhang & Willemijn Hobo & Han J. Bonenkamp & Johannes H. W. Wilt & Marcel J. R. Janssen & Lenn, 2022. "Reprogramming of myeloid cells and their progenitors in patients with non-medullary thyroid carcinoma," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    18. Gaofei Li & Yicong Sun & Immanuel Kwok & Liting Yang & Wanying Wen & Peixian Huang & Mei Wu & Jing Li & Zhibin Huang & Zhaoyuan Liu & Shuai He & Wan Peng & Jin-Xin Bei & Florent Ginhoux & Lai Guan Ng , 2024. "Cebp1 and Cebpβ transcriptional axis controls eosinophilopoiesis in zebrafish," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    19. Hao Li & Zebei Han & Yu Sun & Fu Wang & Pengzhen Hu & Yuang Gao & Xuemei Bai & Shiyu Peng & Chao Ren & Xiang Xu & Zeyu Liu & Hebing Chen & Yang Yang & Xiaochen Bo, 2024. "CGMega: explainable graph neural network framework with attention mechanisms for cancer gene module dissection," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    20. Gregory Farber & Yanhan Dong & Qiaozi Wang & Mitesh Rathod & Haofei Wang & Michelle Dixit & Benjamin Keepers & Yifang Xie & Kendall Butz & William J. Polacheck & Jiandong Liu & Li Qian, 2024. "Direct conversion of cardiac fibroblasts into endothelial-like cells using Sox17 and Erg," Nature Communications, Nature, vol. 15(1), pages 1-17, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-56475-9. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.