Rose, J. T. | Search bioRxiv

bioRxiv2024

Mapping the developmental trajectories of SAP-dependent innate-like gamma delta (γδ) T cells

During thymic development, most {gamma}{delta} T cells acquire innate-like characteristics that are critical for their function in tumor surveillance, infectious disease, and tissue repair. The mechanisms, however, that regulate {gamma}{delta} T cell developmental programming remain unclear. Recently, we demonstrated that the SLAM-SAP signaling pathway regulates the development and function of multiple innate-like {gamma}{delta} T cell subsets. Here, we used a single-cell proteogenomics approach to identify SAP-dependent developmental checkpoints and to define the SAP-dependent {gamma}{delta} TCR repertoire. SAP deficiency resulted in both a significant loss of an immature Gzma+Blk+Etv5+Tox2+{gamma}{delta}T17 precursor population, and a significant increase in Cd4+Cd8+ Rorc+Ptcra+Rag1+ thymic {gamma}{delta} T cells. SAP-dependent diversion of embryonic day 17 thymic {gamma}{delta} T cell clonotypes into the {beta} T cell developmental pathway was associated with a decreased frequency of mature clonotypes in neonatal thymus, and an altered {gamma}{delta} TCR repertoire in the periphery. Finally, we identify TRGV4/TRAV13-4(DV7)-expressing T cells as a novel, SAP-dependent V{gamma}4 {gamma}{delta}T1 subset. Together, the data suggest that SAP-dependent {gamma}{delta}/{beta} T cell lineage commitment regulates {gamma}{delta} T cell developmental programming and shapes the {gamma}{delta} TCR repertoire. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=142 SRC="FIGDIR/small/575073v3_ufig1.gif" ALT="Figure 1"> View larger version (43K): org.highwire.dtl.DTLVardef@1d8b5aeorg.highwire.dtl.DTLVardef@7fd02dorg.highwire.dtl.DTLVardef@13c5c76org.highwire.dtl.DTLVardef@1da72b1_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2019

Mitotic gene bookmarking by RUNX1 contributes to stabilization of the normal mammary epithelial phenotype

RUNX1 has recently been shown to play an important role in determination of mammary epithelial cell identity. However, mechanisms by which loss of the RUNX1 transcription factor in mammary epithelial cells leads to epithelial-to-mesenchymal transition (EMT) are not known. Here, we report mitotic bookmarking of genes by RUNX1 as a potential mechanism to convey regulatory information through successive cell divisions for coordinate control of mammary cell proliferation, growth, and identity. Genome-wide RUNX1 occupancy profiles for asynchronous, mitotically enriched, and early G1 breast epithelial cells reveal RUNX1 is retained during the mitosis to G1 transition on protein coding and long non-coding RNA genes critical for mammary epithelial proliferation, growth, and phenotype maintenance. Disruption of RUNX1 DNA binding and association with mitotic chromosomes alters cell morphology, global protein synthesis, and phenotype-related gene expression. Together, these findings show for the first time that RUNX1 bookmarks a subset of epithelial-related genes during mitosis that remain occupied as cells enter the next cell cycle. Compromising RUNX1 DNA binding initiates EMT, an essential first step in the onset of breast cancer. SignificanceThis study elucidates mitotic gene bookmarking as a potential epigenetic mechanism that impacts breast epithelial cell growth and phenotype and has potential implications in breast cancer onset.

cancer biology↗