Gene module reconstruction identifies cellular differentiation processes and the regulatory logic of specialized secretion in zebrafish

Yiqun Wang; Jialin Liu; Lucia Y Du; Jannik L Wyss; Jeffrey A Farrell; Alexander F Schier

doi:10.1016/j.devcel.2024.10.015

Gene module reconstruction identifies cellular differentiation processes and the regulatory logic of specialized secretion in zebrafish

Dev Cell. 2024 Nov 22:S1534-5807(24)00634-8. doi: 10.1016/j.devcel.2024.10.015. Online ahead of print.

Authors

Yiqun Wang¹, Jialin Liu², Lucia Y Du², Jannik L Wyss³, Jeffrey A Farrell⁴, Alexander F Schier⁵

Affiliations

¹ Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA 02138, USA; Biozentrum, University of Basel, Basel 4056, Switzerland.
² Biozentrum, University of Basel, Basel 4056, Switzerland; Allen Discovery Center for Cell Lineage Tracing, University of Washington, Seattle, WA 98195, USA.
³ Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA 02138, USA.
⁴ Division of Developmental Biology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Bethesda, MD 20892, USA. Electronic address: jeffrey.farrell@nih.gov.
⁵ Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA 02138, USA; Biozentrum, University of Basel, Basel 4056, Switzerland; Allen Discovery Center for Cell Lineage Tracing, University of Washington, Seattle, WA 98195, USA. Electronic address: alex.schier@unibas.ch.

PMID: 39591963
DOI: 10.1016/j.devcel.2024.10.015

Abstract

During differentiation, cells become structurally and functionally specialized, but comprehensive views of the underlying remodeling processes are elusive. Here, we leverage single-cell RNA sequencing (scRNA-seq) developmental trajectories to reconstruct differentiation using two secretory tissues as models-the zebrafish notochord and hatching gland. First, we integrated expression and functional similarities to identify gene modules, revealing dozens of modules representing known and newly associated differentiation processes and their dynamics. Second, we focused on the unfolded protein response (UPR) transducer module to study how general versus cell-type-specific secretory functions are regulated. Profiling loss- and gain-of-function embryos identified that the UPR transcription factors creb3l1, creb3l2, and xbp1 are master regulators of a general secretion program. creb3l1/creb3l2 additionally activate an extracellular matrix secretion program, while xbp1 partners with bhlha15 to activate a gland-like secretion program. Our study presents module identification via multi-source integration for reconstructing differentiation (MIMIR) and illustrates how transcription factors confer general and specialized cellular functions.

Keywords: UPR; bhlha15; creb3l; differentiation processes; functional gene module; hatching gland; notochord; regulatory logic; secretion; xbp1.