The Drosophila histone methyltransferase SET1 coordinates multiple signaling pathways in regulating male germline stem cell maintenance and differentiation

Development. 2024 Aug 1;151(15):dev202729. doi: 10.1242/dev.202729. Epub 2024 Aug 9.

Abstract

Many tissue-specific adult stem cell lineages maintain a balance between proliferation and differentiation. Here, we study how the H3K4me3 methyltransferase Set1 regulates early-stage male germ cells in Drosophila. Early-stage germline-specific knockdown of Set1 results in temporally progressive defects, arising as germ cell loss and developing into overpopulated early-stage germ cells. These germline defects also impact the niche architecture and cyst stem cell lineage non-cell-autonomously. Additionally, wild-type Set1, but not the catalytically inactive Set1, rescues the Set1 knockdown phenotypes, highlighting the functional importance of the methyltransferase activity of Set1. Further, RNA-sequencing experiments reveal key signaling pathway components, such as the JAK-STAT pathway gene Stat92E and the BMP pathway gene Mad, which are upregulated upon Set1 knockdown. Genetic interaction assays support the functional relationships between Set1 and JAK-STAT or BMP pathways, as both Stat92E and Mad mutations suppress the Set1 knockdown phenotypes. These findings enhance our understanding of the balance between proliferation and differentiation in an adult stem cell lineage. The phenotype of germ cell loss followed by over-proliferation when inhibiting a histone methyltransferase also raises concerns about using their inhibitors in cancer therapy.

Keywords: Chromatin; Differentiation; Epigenetic; Gene expression; Germline stem cell; Histone modification; Maintenance; Signaling pathway.

MeSH terms

  • Animals
  • Cell Differentiation* / genetics
  • Cell Lineage / genetics
  • Cell Proliferation / genetics
  • Drosophila Proteins* / genetics
  • Drosophila Proteins* / metabolism
  • Drosophila melanogaster* / genetics
  • Drosophila melanogaster* / metabolism
  • Gene Expression Regulation, Developmental
  • Germ Cells* / cytology
  • Germ Cells* / metabolism
  • Histone-Lysine N-Methyltransferase* / genetics
  • Histone-Lysine N-Methyltransferase* / metabolism
  • Janus Kinases / genetics
  • Janus Kinases / metabolism
  • Male
  • STAT Transcription Factors / genetics
  • STAT Transcription Factors / metabolism
  • Signal Transduction* / genetics
  • Stem Cells / cytology
  • Stem Cells / metabolism

Substances

  • Drosophila Proteins
  • Histone-Lysine N-Methyltransferase
  • STAT Transcription Factors
  • Janus Kinases
  • Stat92E protein, Drosophila