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bioRxiv · 10.64898/2026.08.28.747910

Ectopic expression of the germline transcription factor LSL-1 contributes to developmental delay following failed maternal epigenetic reprogramming

Massenburg, Z.·Nguyen, B. M. T.·Labus, J.·Johnson, S. H.·Blancher, S. D.·Jones, M.·Carpenter, B. S.
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Abstract

Proper transmission of cell identity between generations requires maternal epigenetic reprogramming mechanisms that prevent inappropriate inheritance of lineage-specific transcriptional programs. In Caenorhabditis elegans, loss of the H3K4me1/2 demethylase SPR-5 and the H3K9 methyltransferase MET-2 results in ectopic expression of germline genes in somatic tissues and severe developmental delay. Previous studies demonstrated that the chromatin regulator MES-4 contributes to these defects, but whether germline-specific transcription factors also participate in the ectopic transcriptional program remained unclear. Here, we investigated the role of the germline transcription factor LSL-1 in animals lacking SPR-5 and MET-2. We found that genes normally regulated by LSL-1 in the germline are significantly overrepresented among genes ectopically expressed in the soma of spr-5; met-2 progeny. Consistent with this observation, an endogenously tagged LSL-1 protein became ectopically expressed throughout somatic tissues when maternal SPR-5 and MET-2 activity was disrupted. Furthermore, depletion of LSL-1 partially suppressed the developmental delay observed in spr-5; met-2 mutants. Transcriptomic analyses revealed extensive overlap between MES-4- and LSL-1-dependent transcriptional programs, with most LSL-1-dependent genes also requiring MES-4. Notably, ectopic expression of lsl-1 itself depended on MES-4, suggesting that LSL-1 functions downstream of MES-4. Genes dependent on LSL-1 were strongly enriched for germline-associated expression programs and included previously identified direct LSL-1 targets. Together, our findings support a model in which MES-4 promotes ectopic expression of LSL-1, which in turn contributes to a shared germline-associated transcriptional program and developmental delay following failed maternal epigenetic reprogramming. These results demonstrate how lineage-restricted transcription factors cooperate with inherited chromatin states to reinforce aberrant transcriptional programs and disrupt cell fate boundaries.

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Massenburg, Z., Nguyen, B. M. T., Labus, J., Johnson, S. H., Blancher, S. D., Jones, M., Carpenter, B. S.. 2026-09-03. Ectopic expression of the germline transcription factor LSL-1 contributes to developmental delay following failed maternal epigenetic reprogramming. https://doi.org/10.64898/2026.08.28.747910

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