HDAC1/2-mediated repression of Wnt receptor expression orients asymmetric division polarity in C. elegans

Abstract Asymmetric cell division generates distinct daughter cells essential for tissue development, yet the mechanisms orienting division polarity within tissues remain incompletely understood. Here, we uncover a role for chromatin-mediated transcriptional repression in controlling polarity orientation during asymmetric division of C. elegans epidermal stem cells, known as the seam cells. We show that tissue- specific loss of the class I histone deacetylase hda-1 , homologous to mammalian HDAC1/2, causes reversals in division polarity and reduces molecular asymmetry between daughter cells. Using Targeted DamID to profile HDA-1 genomic occupancy, we identify the Wnt receptors lin-17 /Frizzled and cam-1 /Ror as key targets. Single- molecule FISH reveals that these receptors display striking expression gradients along the body axis, with cam-1 enriched anteriorly and lin-17 posteriorly. In hda-1 mutants, both receptors are upregulated so that differences between seam cells are flattened. Overexpression of either receptor alone is sufficient to reproduce the polarity reversals observed in hda-1 mutants, and their co-overexpression produces additive defects. The polarity phenotype is independent of the canonical NuRD and SIN3 complexes, suggesting that HDA-1 acts through an alternative mechanism to regulate Wnt receptor expression. Our findings establish a direct link between histone deacetylase activity and Wnt receptor expression and support a model in which graded expression of Wnt receptors provides positional cues that orient asymmetric division polarity in response to Wnt signals.