Dissecting the enhancer gene regulatory network in early Drosophila spermatogenesis

Patrick Nierop y Sanchez, Pallavi Santhi Sekhar, Kerem Yildirim, Tim Lange, Laura Zoe Kreplin, Vigneshwarr Muruga Boopathy, Stephanie Rosswag de Souza, Kim Dammer, David Ibberson, Qian Wang, Katrin Domsch, Anniek Stokkermans, Shubhanshu Pandey, Petra Kaspar, Rafael Martinez-Gallegos, Xuefan Gao, Aakriti Singh, Natalja Engel, Fillip Port, Michael Boutros, Josephine Bageritz and Ingrid Lohmann ()
Additional contact information
Patrick Nierop y Sanchez: Department of Developmental Biology and Cell Networks—Cluster of Excellence
Pallavi Santhi Sekhar: Department of Developmental Biology and Cell Networks—Cluster of Excellence
Kerem Yildirim: Department of Developmental Biology and Cell Networks—Cluster of Excellence
Tim Lange: Department of Developmental Biology and Cell Networks—Cluster of Excellence
Laura Zoe Kreplin: Department of Developmental Biology and Cell Networks—Cluster of Excellence
Vigneshwarr Muruga Boopathy: Department of Developmental Biology and Cell Networks—Cluster of Excellence
Stephanie Rosswag de Souza: Department of Developmental Biology and Cell Networks—Cluster of Excellence
Kim Dammer: Department of Developmental Biology and Cell Networks—Cluster of Excellence
David Ibberson: Heidelberg University
Qian Wang: Department of Developmental Biology and Cell Networks—Cluster of Excellence
Katrin Domsch: Department of Developmental Biology and Cell Networks—Cluster of Excellence
Anniek Stokkermans: Hubrecht Institute-KNAW
Shubhanshu Pandey: Department of Developmental Biology and Cell Networks—Cluster of Excellence
Petra Kaspar: Department of Developmental Biology and Cell Networks—Cluster of Excellence
Rafael Martinez-Gallegos: Department of Developmental Biology and Cell Networks—Cluster of Excellence
Xuefan Gao: Department of Developmental Biology and Cell Networks—Cluster of Excellence
Aakriti Singh: Department of Developmental Biology and Cell Networks—Cluster of Excellence
Natalja Engel: Department of Stem Cell Niche Heterogeneity
Fillip Port: Department of Cell and Molecular Biology
Michael Boutros: Department of Cell and Molecular Biology
Josephine Bageritz: Department of Cell and Molecular Biology
Ingrid Lohmann: Department of Developmental Biology and Cell Networks—Cluster of Excellence

Nature Communications, 2025, vol. 16, issue 1, 1-19

Abstract: Abstract Cellular decision-making and tissue homeostasis are governed by transcriptional networks shaped by chromatin accessibility. Using single-nucleus multi-omics, we jointly profile gene expression and chromatin accessibility in 10,335 cells from the Drosophila testis apical tip. This enables inference of 147 cell type-specific enhancer-gene regulons using SCENIC + . We functionally validate key transcription factors, including ovo and klumpfuss, known from other stem cell systems but not previously linked to spermatogenesis. CRISPR-mediated knockout reveals their essential roles in germline stem cell regulation, and we provide evidence that they co-regulate shared targets through overlapping enhancer elements. We further uncover a critical role for canonical Wnt signaling, with Pangolin/Tcf activating lineage-specific targets in the germline, soma, and niche. The Pan eRegulon links Wnt activity to cell adhesion, intercellular signaling and germline stem cell maintenance. Together, our study defines the enhancer-driven regulatory landscape of early spermatogenesis and reveals conserved, combinatorial mechanisms of niche-dependent stem cell control.

Date: 2025
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DOI: 10.1038/s41467-025-62046-9

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